Cephalosporin derivatives, and their application as antibiotics

ABSTRACT

The present invention relates to derivatives of the cephalosporin family, of formula: ##STR1## in which: X is an oxygen atom or a sulfur atom 
     n is zero, 1 or 2. 
     R 1 , R 2  and R 3  each designate, a hydrogen atom or else R 1  and R 2  designate a hydrogen atom or a methyl group, and R 3  designates a carboxyl or cyclopropyl group, or else 
     R 1  and R 2  taken together with the carbon atom to which they are linked form a cyclobutyl or cyclopentyl group and R 3  is a carboxyl group. 
     B is the residue of a primary or secondary amine; 
     their preparation process and application in therapeutics.

This application is a continuation of application Ser. No. 775,667, filed Sept. 13, 1985, now abandoned.

The present invention relates to derivatives of the cephalosporin family, the process for their preparation and their therapeutic use.

The compounds according to the invention correspond to the formula: ##STR2## in which X is an oxygen atom or a sulfur atom

n is zero, 1 or 2.

R₁, R₂ and R₃ each designate, independently a hydrogen atom or else R₁ and R₂ designate a hydrogen atom or a methyl group, and R₃ designates a carboxyl or cyclopropyl group, or else

R₁ and R₂ taken together with the carbon atom to which they are linked form a cyclobutyl or cyclopentyl group and R₃ is a carboxyl group.

B is the residue of a primary or secondary amine selected by the following groups:

Z--NH₂ where Z is an alkylene group with a straight or branched chain having from 2 to 7 carbon atoms, possibly interrupted by a sulfur atom, or else Z is a 1,3-cyclohexylene or 1,4 cyclohexylene group.

Z'--Alk--NH--R where Z' is a 1,2-phenylene or 1,3-phenylene or 1,4-phenylene group possibly substituted by 1, 2 or 3 methyl groups or else Z' is a 1,2-cyclohexylene, 1,3-cyclohexylene or 1,4-cyclohexylene group.

Alk is a straight or branched alkyl group having from 1 to 3 carbon atoms, possibly interrupted by a sulfur atom. R is a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms. ##STR3## where Z" is a 1,3 phenylene or 1,4 phenylene group,

Y is an alkyl group (CH₂)_(m) in which m=1,2 or 3, R' is hydrogen or methyl and R is as defined above,

Z"--CO--NH--Y--NH₂ where Z" and Y are as defined above

Z"--NH--CO--Y--NH₂ where Z' is a 1,3 phenylene or 1,4 phenylene group and Y is an alkyl group (CH₂)_(m) in which m=1,2 or 3.

Z"--Y'--NH--CO--Y--NH₂ where Z" and Y are as defined above and Y' is a straight or branched alkyl group with 1 or 2 carbon atoms ##STR4## where n=0 or 1 and Y is as defined above. a 2-piperidyl, 3-piperidyl or 4-piperidyl group possibly substituted in the nitrogen atom by a --CO--Y--NH₂ group where Y is as defined above.

a group ##STR5## the bicyclic group ##STR6##

Due to the presence in the formula of an oxime group, compounds (I) exist in the two isomeric forms syn and anti. The syn isomers whose therapeutic activity is higher are the preferred compounds.

It is understood that the compound (I) indicated above can exist:

either in the form indicated in Formula (I),

or in tautomeric form (I'): ##STR7## in which B, X, R₁, R₂, R₃ and n are as previously defined.

The salts of the compounds of Formula I (or I') are an integral part of the invention.

They are the salts with pharmaceutically acceptable acids which can form with the amine function of the molecular, as well as the alkaline, alkaline-earth salts, or the amino or aminoacid salts such as triethylamine or the ethanolamines which may form with the carboxyl group in position 4 of the compound (I), or eventually, with the carboxyl group which may be present in the oxime substituent, or else with the 2 carboxylic groups.

The same applies to the readily hydrolyzable or metabolically labile esters derivated from either or both carboxylic groups that may be present in the molecule.

The invention also relates to a process for the preparation of the compounds of Formula (I).

The compounds of Formula I may be prepared pursuant to the following reaction chart: ##STR8##

In these formulae, Tr is a protecting group of the amine function, preferably the trityl group, tBu is the tertiobutyl group, B' is the B group in which the amine function is protected and R'₃ is hydrogen, a cyclopropyl group or a readily labile ester group, and preferably a --COOtBu group. R₁, R₂, R₃, X, n and B are as previously defined.

On compound 1, the B--(CH₂)_(n) --COXH acid or thioacid is reacted; acid or thioacid, of which the amine function has been protected beforehand, according to a known method, with a group such as the tertiobutoxycarbonyl or trichloroethyoxycarbonyl group.

Mostly, the sodium salt of the acid or of the thioacid is used and the reaction is conducted in a suitable solvent such as dimethylformamide or tetrahydrofuranne.

In the case of thioacids, the thioacid itself can be used instead of its salt. Then the reaction is conducted in anhydrous acetone in the presence of potassium bicarbonate and sodium iodide.

With compound 2 obtained in this way, it is possible by the action of phosphorous tribromide at low temperature, in a solvent such as dichloromethane, to eliminate the S-oxide and to obtain compound 3.

Finally, to obtain compound (I), the protecting groups on the amines and the ester(s) are eliminated by a known method, in particular by hydrolysis in acid medium, using for example, trifluoracetic acid or a mixture of formic acid and hydrochloric acid.

Compound (I) is isolated directly in the form of a salt of the B amine group with the strong acid used for deprotection, namely in trifluoracetate or hydrochloride form. It is even possible to transform this salt into another salt of strong acid. To do so, the trifluoracetate or hydrochloride is passed over an ion-exchanging resin in the form of a weak acid (formiate or acetate for example), then the solution is treated with the strong acid from which the salt is to be obtained (for example sulfuric or phosphic acid) and the strong acid is isolated by lyophilization.

With such a salt, it is possible by the action of a base, to obtain the wanted compound of formula (I).

The starting products 1 can be prepared according to known processes and in particular by acylation of 7-amino-3-bromomethyl-3-cepheme-carboxylate or 4-tetriobutyl-1-S-oxide with the acid ##STR9## according to the process described in European Patent No. 60 745.

In the case of thioacids, (X═S), the compounds I (X═S) may be obtained by a second process. This process is summed up in the following reaction diagram: ##STR10##

Starting with the sodium salt of 7-amino-4-cephalosporanic acid, the action of the sodium salt of the protected thioacid B'--(CH₂)_(n) --COSNa is buffered aqueous medium of pH:6.3-6.4 leads to compound 5 suitably substituted in the 3-position.

The carboxylic function being blocked in situ by a trimethylsilyl group, compound 5 is acylated by acid chloride 6. This operation is conducted in solution in the dichloromethane in the presence of triethylamine and dimethylaniline.

The protected derivatives 7 thus obtained leads to derivative (I) (X═S) by acid treatment as indicated in the first process.

The salts and esters of compounds (I) according to the invention are obtained from compounds (I) by reactions known per se.

Thus the inorganic salts are obtained by the action on compounds (I), of an inorganic base such as soda or potash or sodium bicarbonate in an equimolecular amount; the salification reaction is carried out in a solvent such as water or ethanol and the salt obtained in isolated by evaporation of the solution.

The salts of organic bases are obtained by the action on a solution of the acid I in a solvent or a mixture of suitable solvents, of an equimolecular amount of the organic base. The salt is isolated by precipitation with ether.

The esters are obtained by known esterification processes; for example the action of a halogen derivative on a salt such as the sodium salt of the acid will advantageously be used; preferably the reaction will be carried out in a solvent capable of dissolving the starting acid derivative, for example in dimethylformamide.

The syn and anti form isomers are obtained by a suitable choice of reagents.

The following examples enable the scope of the invention to be further understood without however limiting it.

Thus as is usual in this family of compounds, the products according to the invention do not have distinct melting point but only points of decomposition which do not permit them to be characterized.

The products will therefore be characterized by their nuclear magnetic resonance spectrum recorded at 250 MHz, the internal standard being hexamethyldisiloxane. The spectra are recorded in deuteriated dimethylsulfoxide: 10 mg in 0.5 ml. The chemical shifts are measured at ±0.01 ppm and the coupling constants at ±0.5 Hz.

The following abbreviations will be used:

S: singlet

D: doublet

D of D: doublet of doublet

S. e.: widened singlet

M: multiplet

Q: quadruplet

AB: AB system

J: represents the coupling constant.

In addition, elementary microanalyses were carried out in each case and are in agreement with the fomulae indicated.

The infra-red spectra also serve to characterize the products obtained. They were recorded between 4,000 cm⁻¹ and 600 cm⁻¹ from a preparation constituted by a potassium bromide tablet containing the product at a concentration of about 2%; when the spectrum is recorded in solution at 1% in a chlorinate solvent, the nature of the latter is mentioned. The elongation vibration frequency of the carbonyl groups of the molecule is noted (νCO).

EXAMPLE 1

7-[2-(2-amino 4-thiazolyl) 2-(2-carboxy 2-propyl oxyimino) acetamio] 3-(4-piperidyl carbonyloxymethyl) 3-cepheme 4-carboxylic acid bis trifluoroacetate syn isomer. SR 42800. ##STR11##

(a) 7-[2-(2-tritylamino-4-thiazolyl) 2-(2-tertiobutoxycarboxy 2-propyl oxyimino) acetamio] 3-[(1-tertiobutoxycarbonyl 4-piperidyl carbonyloxymethyl)] 3-cepheme 1 β-S-oxide 4-carboxylic of tertiobutyl, syn isomer.

To a solution of 1.38 g of 4-tertiobutyl 1-β-S-oxide 7-[2-(2-tritylamino 4-thiazolyl) 2-(2-tertiobutoxycarbonyl 2-propyl oxyimino)acetamido] 3-bromoethyl 3-cepheme carboxylate syn isomer, in 20 ml of anhydrous dimethylformamide, are added 1 g of 1-tertiobutyloxycarbonyl 4-piperidyl carboxylic acid and 1.5 g of potassium hydrogenocarbonate.

After 17 hours of stirring at ambient temperature (20°-25° C.) the reaction mixture is poured on to 200 ml of ice water. After strong stirring, the crystals are filtered and washed with water. They are taken up with 70 ml of dichloromethane. The organic phase is then washed with a saturated solution of sodium chloride, dried over magnesium sulfate and evaporated. The lacquer obtained is chromatography on a column of 50 g of silica. It is eluted with a dichloromethane-ethyl acetate mixture 90-10 (vol/vol). After evaporation of the fractions containing the compound and trituration in hexane, 1.3 of the expected compound are obtained.

IR Spectrum: νCO

1805 cm⁻¹ : C=0 at 8-position of the β lactam

1735 cm⁻¹ : C=0 of the tertiobutyl esters and of the ester at position 3.

1695 cm⁻¹ : C=0 of the tertiobutoxycarbonyl protecting group of the piperidine and C=0 of the amide at 7-position.

NMR Spectrum at 250 MHz

1H at 8.75 ppm (S, NH Tr) - 1H at 8.10 ppm (D, J=9 Hz, CONH) - 15H at 7.25 ppm (M, H aromatics) - 1H at 6.73 ppm (S, H thiazole) - 1H at 5.81 ppm (M, H₇) - 1H at 5.25 ppm (D, J=13 Hz, CH₂ OCO) - 1H at 4.94 ppm (D, J=4 Hz, H₆) - 1H at 4.55 ppm (D, J=13 Hz, CH₂ OCO) - 1H at 3.90 ppm (D, J=17 Hz, CH₂ SO) - 2H at 3.79 ppm (D, J=12 Hz, HCN Boc equatorials) - 1H at 3.53 ppm (D, J=17 Hz, CH₂ SO) - 2H at 2.75 ppm (M, HCN Box axials) - 1H at 2.50 ppm (M, HCCO₂) - 2H at 1.75 ppm (D, J=12 Hz, HCHCO₂ equatorials) - 9H at 1.46 ppm (S, CO₂ tBu) - 2H at 1.40 ppm (M, HCCHCO₂ axials) - 6H at 1.39 ppm (S, CH₃)₂ C) - 9H at 1.36 ppm (S, CO₂ tBu) - 9H at 1.29 ppm (S, Boc N).

(b) 7-[2-(2-tritylamino-4-thiazolyl) 2-(2-tertiobutoxycarboxy 2-propyl oxyimino) acetamio] 3-[(1-tertiobutoxycarbonyl 4-piperidyl carbonyloxymethyl)] 3-cepheme 4-carboxylic of tertiobutyl, syn isomer.

To the solution composed of 1 g of the compound obtained above and 20 ml of methylene chloride cooled down to -20° C., is added in 5 minutes, a solution of 0.15 ml of phosphorous tribromide in 20 ml of methylene chloride. Keeping the temperature down to -20° C., the mixture is stirred for 15 minutes and 100 ml of a 5% solution of sodium bicarbonate in water are added. The resulting mixture is stirred for three hours at 0° C. then the organic phase is decanted and dried over magnesium sulphate.

The solvent is evaporated in vacuo and the residual is chromatographied on silica with elution with a mixture of methylene chloride and methanol 100-0.5 vol/vol. After evaporation of the solvent, the crude product is used as in the next operation.

(c) SR 42800

The product obtained from the preceding operation is placed in solution in 15 ml of trifluoracetic acid. After 45 minutes at 25° C., the acid is evaporated in vacuo without heating and the residual is taken up in ether. The crystals are drained and washed with ether.

The expected product is obtained, after drying.

NMR Spectrum

1H at 9.45 ppm (D,J=9 Hz, --CO--NH) - 1H at 8.65 ppm and 1at 8.40 ppm (S.e., NH₂ ⁺ piperidinium) - 2H at 7.30 ppm (S.E. NH₂ thiazole) - 1H at 6.70 ppm (S, H thiazole) - 1H at 5.80 ppm (D of D, J₁ =9 Hz J₂ =4 Hz H₂) - 1H at 5.10 ppm (D, J=4 Hz, H₆) - 2H at 4.99 and 4.70 ppm (D, J=13 Hz, CH₂ OCO) - 2H at 3.52 ppm (AB, J_(AB) =17 Hz, CH₂ -S) - 2H at 3.25 ppm (M, HαN piperidine) - 2H at 2.90 ppm (M, HαN piperidine) - 1H at 2.63 ppm (M, HC>-COO) - 2H at 1.95 ppm (M, Hβ N piperidine) - 2H at 1.70 ppm (Hβ N piperidine) - 6H at 1.40 ppm (2S (CH₃)₂ --C--).

EXAMPLES 2 to 63

Operating as in Example 1, the compounds according to the invention are prepared in trifluoracetate form, as described in table 1, hereafter. ##STR12##

These compounds are identified by a reference number. For each one, the values of R₁, R₂, R₃, B and n and the NMR spectrum are given.

For 3, the last intermediate product before deblocking the acid and amine functions of the molecular, the characteristics of the infrared spectrum are also given. The wavelengths indicated in cm⁻¹ correspond, to the elongation vibration frequencies of the carbonyl at position 8 of the beta lactam, of the tertiobutylic esters and of the ester in position 3, of the amide in position 7 and of the carbamate protecting the amide, in this order. When only two wavelengths are indicated, the second corresponds to a wide band covering the elongation vibration frequencies of, altogether, the esters, the amide and the carbomate protecting the amine.

The list of the NMR spectra of the compounds cited in Table I is given after the Table.

                                      TABLE I                                      __________________________________________________________________________                                         IR                                                                             Intermediate 3                             SR No.                                                                             n R.sub.1                                                                           R.sub.2                                                                           R.sub.3                                                                             B                  γCO cm.sup.-1                                                                    NMR No.                            __________________________________________________________________________     42 796                                                                             0 CH.sub.3                                                                          CH.sub.3                                                                          COOH (CH.sub.2).sub.2NH.sub.2                                                                          1795-1725                                                                              1                                                                      1690                                       42 797                                                                             0 CH.sub.3                                                                          CH.sub.3                                                                          COOH (CH.sub.2).sub.3NH.sub.2                                                                          1795-1725                                                                              2                                                                      1690                                       42 798                                                                             0 CH.sub.3                                                                          CH.sub.3                                                                          COOH (CH.sub.2).sub.4NH.sub.2                                                                          1790-1725                                                                              3                                                                      1690                                       42 799                                                                             0 CH.sub.3                                                                          CH.sub.3                                                                          COOH                                                                                 ##STR13##         1795-1720                                                                              4                                  42 801                                                                             0 CH.sub.3                                                                          CH.sub.3                                                                          COOH                                                                                 ##STR14##         1790-1725                                                                              5                                  42 803                                                                             0 CH.sub.3                                                                          CH.sub.3                                                                          COOH                                                                                 ##STR15##         1790-1720                                                                              6                                  42 804                                                                             0 CH.sub.3                                                                          CH.sub.3                                                                          COOH                                                                                 ##STR16##         1790-1720                                                                              7                                  42 805                                                                             0 CH.sub.3                                                                          CH.sub.3                                                                          COOH                                                                                 ##STR17##         1790-1720                                                                              8                                  42 806                                                                             0 CH.sub.3                                                                          CH.sub.3                                                                          COOH                                                                                 ##STR18##         1795-1725                                                                              9                                  42 807                                                                             0 CH.sub.3                                                                          CH.sub.3                                                                          COOH                                                                                 ##STR19##         1795-1725                                                                              10                                 42 808                                                                             0 CH.sub.3                                                                          CH.sub.3                                                                          COOH                                                                                 ##STR20##         1790-1715                                                                              11                                 42 809                                                                             0 CH.sub.3                                                                          CH.sub.3                                                                          COOH                                                                                 ##STR21##         1795-1710                                                                              12                                 42 810                                                                             0 CH.sub.3                                                                          CH.sub.3                                                                          COOH                                                                                 ##STR22##         1790-1720                                                                              13                                 42 883                                                                             0 H  H  H                                                                                    ##STR23##         1790-1720 1690                                                                         14                                 42 885                                                                             0 H  H  H                                                                                    ##STR24##         1790-1715                                                                              15                                 42 893                                                                             0 H  H  H                                                                                    ##STR25##         1790-1720                                                                              16                                 42 895                                                                             0 H  H  H                                                                                    ##STR26##         1790-1715 1655 (CH.sub.2 Cl.sub.2)                                                     17                                 42 897                                                                             1 H  H  H                                                                                    ##STR27##         1790-1725 1680 (CH.sub.2 Cl.sub.2)                                                     18                                 42 898                                                                             0 H  H  H    CH.sub.2 SCH.sub.2 CH.sub.2 NH.sub.2                                                              1790-1715                                                                              19                                                                     (CH.sub.2 Cl.sub.2)                        42 877                                                                             0 CH.sub.3                                                                          CH.sub.3                                                                          COOH                                                                                 ##STR28##         1790-1720                                                                              20                                 42 879                                                                             0 CH.sub.3                                                                          CH.sub.3                                                                          COOH CH.sub.2 SCH.sub.2 CH.sub.2 NH.sub.2                                                              1790-1715                                                                              21                                                                     (CH.sub.2 Cl.sub.2)                        42 880                                                                             1 CH.sub.3                                                                          CH.sub.3                                                                          COOH                                                                                 ##STR29##         1790-1720 1680-(CH.sub.2 Cl.sub.2)                                                     22                                 42 881                                                                             0 CH.sub.3                                                                          CH.sub.3                                                                          COOH                                                                                 ##STR30##         1790-1720 (CH.sub.2 Cl.sub.2)                                                          23                                 42 942                                                                             0 CH.sub.3                                                                          CH.sub.3                                                                          COOH                                                                                 ##STR31##         1790-1720                                                                              24                                 42 946                                                                             0 H  H  H                                                                                    ##STR32##         1790-1720                                                                              25                                 42 950                                                                             0 H  H  H                                                                                    ##STR33##         --      26                                 42 961                                                                             0 CH.sub.3                                                                          CH.sub.3                                                                          COOH                                                                                 ##STR34##         1790-1720  1680                                                                        27                                 42 963                                                                             0 CH.sub.3                                                                          CH.sub.3                                                                          COOH                                                                                 ##STR35##         1790-1725                                                                              28                                 42 965                                                                             0 H  H  H                                                                                    ##STR36##         1790-1725 1685                                                                         29                                 42 971                                                                             0 H  H  H                                                                                    ##STR37##         --      30                                 43 013                                                                             0 CH.sub.3                                                                          CH.sub.3                                                                          COOH                                                                                 ##STR38##         1790-1720                                                                              31                                 43 016                                                                             0                                                                                 ##STR39##                                                                           COOH                                                                                 ##STR40##         1795-1725                                                                              32                                 43 029                                                                             0 H  H  H                                                                                    ##STR41##         1785-1700                                                                              33                                 43 948                                                                             0 H  H  H                                                                                    ##STR42##         1790-1720                                                                              34                                 42 147                                                                             0 H  H  H                                                                                    ##STR43##         1790-1725 1625                                                                         35                                 43 179                                                                             0 H  H  H                                                                                    ##STR44##         1790-1720                                                                              36                                 43 183                                                                             0 H  H  H                                                                                    ##STR45##         1790-1720                                                                              37                                 43 185                                                                             0 H  H  H                                                                                    ##STR46##         1790-1720                                                                              38                                 43 187                                                                             0 H  H  H                                                                                    ##STR47##         1790-1715                                                                              39                                 43 189                                                                             0 H  H  H                                                                                    ##STR48##         1790-1710                                                                              40                                 43 224                                                                             1 H  H  H                                                                                    ##STR49##         1790-1725 1680 (CH.sub.2 Cl.sub.2)                                                     41                                 43 226                                                                             1 H  H  H                                                                                    ##STR50##         1790- 1725 1680 (CH.sub.2 Cl.sub.2)                                                    42                                 43 228                                                                             0 H  H  H                                                                                    ##STR51##         1790-1720 1685                                                                         43                                 43 230                                                                             0 H  H  H                                                                                    ##STR52##         1785-1720                                                                              44                                 43 232                                                                             1 H  H  H                                                                                    ##STR53##         1785-1715 1685                                                                         45                                 43 323                                                                             0 H  H  H                                                                                    ##STR54##         1790-1720                                                                              46                                 43 325                                                                             0 H  H  H                                                                                    ##STR55##         1790-1720 1675                                                                         47                                 43 329                                                                             0 CH.sub.3                                                                          CH.sub.3                                                                          COOH                                                                                 ##STR56##         1790-1720                                                                              48                                 43 330                                                                             0 H  H  H                                                                                    ##STR57##         1785-1715                                                                              49                                 43 334                                                                             0 CH.sub.3                                                                          CH.sub.3                                                                          COOH                                                                                 ##STR58##         1790-1715                                                                              50                                 43 336                                                                             0 H  H  H                                                                                    ##STR59##         1785-1720                                                                              51                                 43 338                                                                             0 H  H  H                                                                                    ##STR60##         1785-1720                                                                              52                                 43 415                                                                             1 H  H                                                                                  ##STR61##                                                                           ##STR62##         1780-1720 1680 (CH.sub.2 Cl.sub.2)                                                     53                                 43 417                                                                             0 H  H  H    (CH.sub.2).sub.5 NH.sub.2                                                                         1790-1720                                                                              54                                 43 419                                                                             0 H  H  H    (CH.sub.2).sub. 7 NH.sub.2                                                                        1790-1715                                                                              55                                                                     (CH.sub.2 Cl.sub.2)                        43 464                                                                             2 H  H  H                                                                                    ##STR63##         1785-1720 1665 (CH.sub.2 Cl.sub.2)                                                     56                                 43 465                                                                             2 CH.sub.3                                                                          CH.sub.3                                                                          COOH                                                                                 ##STR64##         1785-1720 1675 (CH.sub.2 Cl.sub.2)                                                     57                                 43 559                                                                             2 H  H  H                                                                                    ##STR65##         1790-1720 1680 (CH.sub.2 Cl.sub.2)                                                     58                                 43 561                                                                             2 CH.sub.3                                                                          CH.sub.3                                                                          COOH                                                                                 ##STR66##         1790-1720 1675 (CH.sub.2 Cl.sub.2)                                                     59                                 43 563                                                                             0 CH.sub.3                                                                          CH.sub.3                                                                          COOH                                                                                 ##STR67##         1785-1720 1685 (CH.sub.2 Cl.sub.2)                                                     60                                 43 666                                                                             0 H  H  H                                                                                    ##STR68##         1785-1715  1685 (CH.sub.2 Cl.sub.2)                                                    61                                 43 668                                                                             0 CH.sub.3                                                                          CH.sub.3                                                                          COOH                                                                                 ##STR69##         1785-1715 1685 (CH.sub.2 Cl.sub.2)                                                     62                                 __________________________________________________________________________

NMR n° 1

1H at 9.41 ppm (D, J=9 Hz, CO--NH) - 3H at 7.86 ppm (S.e., N⁺ H₃) - 2H at 7.30 ppm (S.e. NH₂ thiazole) - 1H at 6.71 ppm (S, H thiazole) - 1H at 5.80 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇) - 1H at 5.09 ppm (D, J=4 Hz, H₆) - 1H at 5.05 ppm and 1H at 4.72 ppm (D, J=13 Hz, CH₂ OCO) - 2H at 3.51 ppm (AB, J_(AB) =17 Hz, CH₂ S) - 2H at 3.00 ppm (M, CH₂ --N⁺ H₃) - 2H at 2.62 ppm (T, J=7 Hz, CH₂ --CH₂ --N⁺) - 6H at 1.42 ppm (2S, (CH₃)₂ --C).

NMR n° 2

1H at 9.45 ppm (D, J=9 Hz, CONH) - 3H at 7.75 ppm (S.e., CH₂ N⁺ H₃) - 2H at 7.45 ppm (S.e. NH₂ thiazole) - 1H at 6.70 ppm (S, H thiazole) - 1H at 5.80 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇) - 1H at 5.14 ppm (D, J=4 Hz, H₆) - 1H at 5.05 ppm and 1H at 4.69 ppm (D, J=13 Hz, CH₂ OCO) - 2H at 3.52 ppm (AB, J_(AB) =17 Hz, CH₂ S) - 2H at 2.75 ppm (M, CH₂ N⁺) - 2H at 2.40 ppm (M, OCOCH₂) - 2H at 1.75 ppm (M, CH₂ --CH₂ N⁺) - 6H at 1.40 ppm (2S, (CH₃)₂ --C).

NMR n° 3

1H at 9.45 ppm (D, J=9 Hz, CONH) - 3H at 7.70 ppm (S.e., CH₂ N⁺ H₃) - 2H at 7.45 ppm (S.e. NH₂ thiazole) - 1H at 6.70 ppm (S, H thiazole) - 1H at 5.80 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇) - 1H at 5.13 ppm (D, J=4 Hz, H₆) - 1H at 4.98 ppm and 1H at 4.65 ppm (D, J=13 Hz, CH₂ OCO) - 2H at 3.52 ppm (AB, J_(AB) =17 Hz, CH₂ S) - 2H at 2.75 ppm (M, CH₂ N⁺) - 2H at 2.35 ppm (M, OCOCH₂) - 4H at 1.50 ppm (M, CH₂ --CH₂ --CH₂ N⁺) - 6H at 1.40 ppm (2S, (CH₃)₂ --C).

NMR n° 4

1H at 9.45 ppm (D, J=9 Hz, CONH) - 3H at 7.95 ppm (S.e., CH₂ N⁺ H₃) - 2H at 7.40 ppm (S.e. NH₂ thiazole) - 1H at 6.70 ppm (S, H thiazole) - 1H at 5.82 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇) - 1H at 5.13 ppm (D, J=4 Hz, H₆) - 1H at 5.05 ppm and 1H at 4.70 ppm (D, J=13 Hz, CH₂ OCO) - 2H at 3.55 ppm (AB, J_(AB) =17 Hz, CH₂ S) - 2H at 2.95 ppm (M, CH₂ ⁺ N) - 6H at 1.40 ppm (2S, (CH₃)₂ C--ON) - 6H at 1.15 ppm (S, (CH.sub. 3)₂ C--CH₂).

NMR n° 5

1H at 9.45 ppm (D, J=9 Hz, CONH) - 3H at 7.70 ppm (S.e., CH₂ --N⁺ H₃) - 2H at 7.45 ppm (S.e. NH₂ thiazole) - 1H at 6.70 ppm (S, H thiazole) - 1H at 5.82 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇) - 1H at 5.10 ppm (D, J=4 Hz, H₆) - 1H at 4.98 ppm and 1H at 4.65 ppm (D, J=13 Hz, CH₂ OCO) - 2H at 3.55 ppm (AB, J_(AB) =17 Hz, CH₂ S) - 2H at 2.65 ppm (M, CH₂ N⁺) - 1H at 2.25 ppm (M, OCOCH₂) - 4H at 1.90 ppm (M, cyclohexane) - 4 H at 1.25 ppm (M, cyclohexane) - 6H at 1.40 ppm (2S, (CH₃)₂ C) - 2H at 1.00 ppm (cyclohexane) - :

NMR n° 6

1H at 9.42 ppm (D, J=9 Hz, NHCO) - 3H at 8.30 ppm (S.e., CH₂ N⁺ H₃) - 2H at 8.00 ppm (D, J=8 Hz, H aromatics ortho CO₂) - 2H at 7.55 ppm (D, J=8 Hz, H aromatics meta CO₂) - 2H at 7.30 (S.e., NH₂ thiazole) - 1H at 6.70 ppm (S, H thiazole) - 1H at 5.84 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇) - 1H at 5.16 ppm (D, J=4 Hz, H₆) - 1H at 4.82 ppm (D, J=13 Hz, OCOCH₂) - 1H at 5.25 ppm (D, J=13 Hz, O CO CH₂) - 2H at 4.08 ppm (M, Ar-- CH₂ --NH₂) - 2H at 3.67 ppm (AB, J_(AB) =17 Hz, CH₂ S) - 6H at 1.42 ppm (2S, (CH₃)₂ --Cl) - .

NMR n° 7

1H at 9.45 ppm (D, J=9 Hz, CONH) - 3H at 8.25 ppm (S.e., CH₂ N⁺ H₃) - 1H at 8.05 ppm (S, H aromatic ortho CO₂ and ortho CH₂ NH₂) - 1H at 7.95 ppm (D, J=8 Hz, H aromatic para CH₂ NH₂) - 1at 7.70 ppm (D, J=8 Hz, H aromatic para CO₂) - 1H at 7.55 ppm (T, J=8 Hz, H aromatic meta CO₂) - 2H at 7.40 (S.e., NH₂ thiazole) - 1H at 6.70 ppm (S, H thiazole) - 1H at 5.85 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇) - 1H at 5.25 ppm (D, J=13 Hz, CH₂ OCO) - 1H at 5.15 ppm (D, J=4 Hz, H₆) - 1H at 4.95 ppm (D, J=13 Hz, CH₂ OCO) - 2H at 4.10 ppm (M, Ar CH₂ N) - 2H at 3.70 ppm (AB, J_(AB) =17 Hz, CH₂ S) - 6H at 1.40 ppm (2S, (CH₃)₂ --C) - .

NMR n° 8

1H at 9.45 ppm (D, J=9 Hz, CONH) - 3H at 8.25 ppm (S.e., CH₂ N⁺ H₃) - 1H at 7.70 ppm (D, J=8 Hz, H aromatic ortho CO₂) - 1H at 7.55 ppm (D, J=8 Hz, H aromatic para CO₂) - 1H at 7.35 ppm (T, J=8 Hz, H aromatic meta CO₂) - 2H at 7.30 (se, NH₂ thiazole) - 1H at 6.70 ppm (S, H thiazole) - 1H at 5.85 ppm (D de D, J₁ =9 Hz J₂ =4 Hz, H₇) - 1H at 5.17 ppm (M, H₆ CH₂ OCO) - 1H at 4.90 ppm (D, J=13 Hz, CH₂ OCO) - 2H at 4.08 ppm (M, Ar CH₂ N) - 2H at 3.65 ppm (AB, J_(AB) =17 Hz, CH₂ S) - 3H at 2.40 ppm (S, CH₃ --Ar) - 6H at 1.40 ppm (2S, (CH₃)₂ --C) - .

NMR n° 9

1H at 9.45 ppm (D, J=9 Hz, NHCO) - 3H at 8.15 ppm (S.e., CH₂ NH₃ ⁺) - 2H at 7.40 ppm (S.e., NH₂ thiazole) - 1H at 7.30 ppm (D, J=8 Hz, H aromatic para CO₂) - 1H at 7.15 ppm (D, J=8 Hz, H aromatic meta CO₂) - 1H at 6.70 ppm (S, H thiazole) - 1H at 5.85 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇) - 2H at 5.15 ppm (M, H₆ CH₂ OCO) - 1H at 4.98 ppm (D, J=13 Hz, CH₂ OCO) - 2H at 4.00 ppm (M, Ar CH₂ N) - 2H at 3.60 ppm (AB, J_(AB) =17 Hz, CH₂ S) - 2H at 2.20 ppm (S, 2CH₃ --Ar) - 6H at 1.40 ppm (2S, (CH₃)₂ --C) - .

NMR n° 10

1H at 9.43 ppm (D, J=9 Hz, CONH) - 3H at 8.00 ppm (S.e., CH₂ --N⁺ H₃) - 2H at 7.40 ppm (S.e., NH₂ thiazole) - 1H at 7.00 ppm (S, H aromatic) - 1H at 6.70 ppm (S, H thiazole) - 1H at 5.85 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇) - 2H at 5.15 ppm (M, H₆ CH₂ OCO) - 1H at 5.00 ppm (D, J=13 Hz, CH₂ OCO) - 2H at 4.00 ppm (M, CH₂ N) - 2H at 3.55 ppm (AB, J_(AB) =17 Hz, CH₂ S) - 2H at 2.20 ppm (S, CH₃ Ar) - 3H at 2.25 ppm (S, CH₃ Ar) - 3H at 2.75 ppm (S, CH₃ Ar) - 6H at 1.40 ppm (2S (CH₃)₂ --C) - .

NMR n° 11

1H at 10.8 ppm (S, Ar NHCO) - 1H at 9.45 ppm (D, J=9 Hz, NHCO) - 3H at 8.15 ppm (S.e., CH₂ N⁺ H₃) - 1H at 7.30 ppm (D, J=8 Hz, H aromatics ortho CO₂) - 2H 7.67 ppm (D, J=8 Hz, H aromatics meta CO₂) - 2H at 7.45 ppm (S.e., NH₂ thiazole) - 1H at 6.70 ppm (S, H thiazole) - 1H at 5.81 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇) - 2H at 5.20 ppm (M, H₆ CH₂ OCO) - 1H at 4.87 ppm (D, J=13 Hz, CH₂ OCO) - 2H at 3.80 ppm (M, COCH₂ N) - 2H at 3.68 ppm (AB, J_(AB) =17 Hz, CH₂ S) - 6H at 1.43 ppm (2S, (CH₃)₂ --C) - .

NMR n° 12

1H at 10.46 ppm (S, Ar NHCO) - 1H at 9.40 ppm (D, J=9 Hz, CONH) - 2H at 7.92 ppm (D, J=8 Hz, H aromatics ortho CO₂) - 5H at 7.75 ppm (M, CH₂ N⁺ H₃ and H aromatics meta CO₂) - 2H at 7.25 ppm (S.e., NH₂ thiazole) - 1H at 6.71 ppm (S, H thiazole) - 1H at 5.83 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇) - 2H at 5.20 ppm (M, H₆ and CH₂ OCO) - 1H at 4.88 ppm (D, J=13 Hz, CH₂ OCO) - 2H at 3.65 ppm (AB, J_(AB) =17 Hz, CH₂ S) - 2H at 3.05 ppm (M, CH₂ CH₂ N) - 2H at 2.72 ppm (T, J=7 Hz, CH₂ CH₂ N) - 6H at 1.40 ppm (2S, (CH₃)₂ --C) - .

NMR n° 13

1H at 10.70 ppm (S, Ar NHCO) - 1H at 9.40 ppm (D, J=9 Hz, CONH) - 4H at 8.18 ppm (S.e., CH₂ N⁺ H₃ and H aromatic ortho CO₂ and ortho NH) - 1H at 7.85 ppm (D, J=8 Hz, H aromatic para NH) - 1H at 7.67 ppm (D, J=8 Hz, H aromatic para CO₂) - 1H at 7.50 ppm (T, J=8 Hz, H aromatics meta CO₂) - 1H at 6.70 ppm (S, H thiazole) - 1H at 5.80 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇) - 1H at 5.25 ppm (D, J=13 Hz, CH₂ OCO) - 1H at 5.15 ppm (D, J=4 Hz, H₆ ) - 1H at 4.90 ppm (D, J=13 Hz, CH₂ OCO) - 2H at 3.75 ppm (M, CO--CH₂ --N) - 2H at 3.68 ppm (AB, J_(AB) =17 Hz, CH₂ S) - 6H at 1.43 ppm (2S, (CH₃)₂ --C) - .

NMR n° 14

1H at 10.70 ppm (S, Ar NHCO) - 1H at 9.55 ppm (D, J=9 Hz, NH--CO) - 4H at 8.18 ppm (S.e., CH₂ N⁺ H₃, H aromatic ortho CO₂ and ortho NH) - 1H at 7.82 ppm (D, J=8 Hz, H aromatic para NH) - 1H at 7.72 ppm (D, J=8 Hz, H aromatic para CO₂) - 1H at 7.50 ppm (T, J=8 Hz, H aromatics meta CO₂) - 2H at 7.20 ppm (S.e., NH₂ thiazole) - 1H at 6.69 ppm (S, H thiazole) - 1H at 5.80 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇) - 1H at 5.25 ppm (D, J=13 Hz, CH₂ OCO) - 1H at 5.15 ppm (D, J=4 Hz, H₆) - 1H at 4.93 ppm (D, J=13 Hz, CH₂ OCO) - 5H at 3.80 ppm (2S, CH₃ ON and COCH₂ N) - 2H at 3.63 ppm (AB, J_(AB) =17 Hz, CH₂ S) - .

NMR n° 15

1H at 10.80 ppm (S, Ar--NH--CO) - 1H at 9.55 ppm (D, J=9 Hz, CONH) - 3H at 8.20 ppm (S.e., CH₂ N⁺ H₃) - 2H at 7.95 ppm (D, J=8 Hz, H aromatic ortho CO₂) - 2H at 7.70 (D, J=8 Hz, H aromatic meta CO₂) - 2H at 7.20 ppm (S.e., NH₂ thiazole) - 1H at 6.70 ppm (S, H thiazole) - 1H at 5.75 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇) - 1H at 5.20 ppm (D, J=13 Hz, CH₂ OCO) - 1H at 5.10 ppm (D, J=4 Hz, H₆) - 1H at 4.92 ppm (D, J=13 Hz, CH.sub. 2 OCO) - 5H at 3.85 ppm (S.e., N--OCH₃ and COCH₂ N) - 2H at 3.60 ppm (AB, J_(AB) =17 Hz, CH₂ S) - .

NMR n° 16

1H at 9.60 ppm (D, J=9 Hz, NHCO) - 3H at 8.30 ppm (S.e., CH₂ N⁺ H₃) - 2H at 7.97 ppm (D, J=8 Hz, H aromatics ortho CO₂) - 2H at 7.55 ppm (D, J=8 Hz, H aromatics meta CO₂) - 2H at 7.20 ppm (S.e., NH₂ thiazole) - 1H at 6.70 ppm (S, H thiazole) - 1H at 5.75 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇) - 1H at 5.25 ppm (D, J=13 Hz, CH₂ OCO) - 1H at 5.13 ppm (D, J=4 Hz, H₆) - 1H at 4.93 ppm (D, J=13 Hz, CH₂ OCO) - 2H at 4.09 ppm (M, Ar CH₂ N) - 3H at 3.80 ppm (S, CH₃ ON) - 2H at 3.66 ppm (AB, J_(AB) =17 Hz, CH₂ S) - .

NMR n° 17

1H at 9.55 ppm (D, J=9 Hz, CONH) - 3H at 8.00 ppm (S.e., CH₂ N⁺ H₃) - 1H at 6.70 ppm (S, H thiazole) - 1H at 5.76 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇) - 1H at 5.09 ppm (D, J=4 Hz, H₆) - 1H at 4.97 ppm and 1H at 4.68 ppm ((D, J=13 Hz, CH₂ OCO) - 1H at 4.12 ppm (M, H piperidine α N equatorial) - 5H at 3.80 ppm (M, CH₃ ON et CO--CH₂ N) - 3H at 3.50 ppm (M, CH₂ S et H piperidine α N equatorial) - 1H at 3.05 ppm (M, H piperidine α N axial) - 1H at 2.80 ppm (M, H piperidine α N axial) - 1H at 2.66 ppm (M, H piperidine γ N) - 2H at 1.85 ppm and 2H at 1.50 ppm (M, H piperidine β N) - .

NMR n° 18

1H at 9.55 ppm (D, J=9 Hz, NHCO) - 1H at 8.50 ppm and 1H at 8.40 ppm (S.e., N⁺ H₂ piperidinium) - 2H at 7.30 ppm (S.e., NH₂ thiazole) - 1H at 6.70 ppm (S, H thiazole) - 1H at 5.75 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇) - 1H at 5.08 ppm (D, J=4 Hz, H₆) - 1H at 4.95 ppm 1H at 4.56 ppm (D, J=13 Hz, CH₂ OCO) - 3H at 3.80 ppm (S, CH₃ ON) - 2H at 3.50 ppm (AB, J_(AB) =17 Hz, CH₂ S) - 2H at 3.15 (M, H piperidine α N equatorial) - 2H at 2.65 ppm (M, H piperidine α N axial) - 2H at 2.36 ppm (M, OCOCH₂) - 1H at 2.00 ppm (M, H piperidine CH₂ --HC<) - 4H between 1.2 and 1.7 ppm (M, H piperidine β et γ N) - .

NMR n° 19

1H at 9.58 ppm (D, J=9 Hz, NHCO) - 3H at 7.80 ppm (S.e., CH₂ NH₃ ⁺) - 1H at 6.71 ppm (S, H thiazole) - 1H at 5.75 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇) - 1H at 5.10 ppm (D, J=4 Hz, H₆) - 1H at 5.03 ppm 1H at 4.75 ppm (D, J=13 Hz, CH₂ OCO) - 3H at 3.84 ppm (S, CH₃ ON) - 1H at 3.60 ppm (D, J=17 Hz, CH₂ S) - 3H at 3.48 ppm (M, CH_(S) S et OCOCH₂ S) - 2H at 3.00 ppm (M, CH₂ N⁺ H₃) - 2H at 2.75 ppm (T, J=7 Hz, CH₂ --CH₂ --N⁺ H₃) - .

NMR n° 20

1H at 12.80 ppm (S.e., thiazole-NHCO) - 1H at 9.45 ppm (D, J=9 Hz, NHCO) - 3H at 8.40 ppm (S.e., CH₂ N⁺ N₃) - 1H at 8.20 ppm (S, H thiazole ester) - 2H at 7.40 (S.e., NH₂ thiazole) - 1H at 6.68 ppm (S, H thiazole amine) - 1H at 5.88 ppm (D de D, J₁ =9 Hz J₂ =4 Hz, H₇) - 2H at 5.20 ppm (M, H₆ and CH₂ OCO) - 1H at 4.90 ppm (D, J=13 Hz, CH₂ OCO) - 2H at 3.84 ppm (S.e., COCH₂ N) - 2H at 3.61 ppm (AB, J_(AB) =17 Hz, CH₂ S) - 6H at 1.42 ppm (2S, (CH₃)₂ C) - .

NMR n° 21

1H at 9.40 ppm (D, J=9 Hz, CONH) - 3H at 7.80 ppm (S.e., CH₂ N⁺ H₃) - 2H at 7.40 ppm (S.e., NH₂ thiazole) - 1H at 6.68 ppm (S, H thiazole) - 1H at 5.85 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇) - 1H at 5.13 ppm (D, J=4 Hz, H₆) - 1H at 5.04 ppm and 1H at 4.75 ppm (D, J=13 Hz, CH₂ OCO) - 1H at 3.60 ppm (D, J=17 Hz, CH₂ S) - 3H at 3.50 ppm (M, CH₂ S et OCOCH₂ S--) - 2H at 2.98 ppm (M, CH₂ N) - 2H at 2.75 ppm (M, CH₂ CH₂ N) - 6H at 1.42 ppm (2S, (CH₃)₂ C) - .

NMR n° 22

1H at 9.40 ppm (D, J=9 Hz, NHCO) - 1H at 8.60 ppm and 1H at 8.40 ppm (S.e., N⁺ H₂ piperidinium) - 1H at 6.70 ppm (S, H thiazole) - 1H at 5.83 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇) - 1H at 5.12 ppm (D, J=4 Hz, H₆) - 1H at 4.95 ppm and 1H at 4.67 ppm (D, J=13 Hz, CH₂ OCO) - 2H at 3.50 ppm (AB, J_(AB) =17 Hz, CH₂ S) - 2H at 3.20 (M, H piperidine α N equatorial) - 2H at 2.60 ppm (M, H piperidine α N axial) - 2H at 2.30 ppm (M, OCOCH₂) - 1H at 2.05 ppm (M, H piperidine --HC<) - 4H between 1.90 and 1.20 ppm (M, H piperidine β and γ N) - 6H at 1.44 ppm (2S, (CH₃)₂) - .

NMR n° 23

1H at 9.45 ppm (D, J=9 Hz, NHCO) - 3H at 8.00 ppm (S.e., CH₂ N⁺ H₃) - 1H at 6.73 ppm (S, H thiazole) - 1H at 5.84 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇) - 1H at 5.16 ppm (D, J=4 Hz, H₆) - 1H at 5.00 ppm et 1H at 4.66 ppm (D, J=13 Hz, CH₂ OCO) - 1H at 4.16 ppm (M, H piperidine α N equatorial) - 2H at 3.80 ppm (M, COCH₂ N) - 3H at 3.55 (M, CH₂ S et H piperidine α N equatorial) - 1H at 3.05 ppm (M, H piperidine α N axial) - 1H at 2.80 ppm (M, H piperidine α N axial) - 1H at 2.67 ppm (M, H piperidine γ N) - 2H at 1.85 ppm and 2H at 1.50 ppm (M, H piperidine β N) - 6H at 1.44 ppm (2S, (CH₃)₂ C) - .

NMR n° 24

1H at 9.40 ppm (D, J=9 Hz, CONH) - 2H at 7.85 ppm (D, J=8 Hz, H aromatics ortho CO₂) - 3H at 7.70 ppm (S.e., CH₂ N⁺ H₃) - 2H at 7.50 ppm (D, J=8 Hz, H aromatics meta CO₂) - 1H at 6.70 ppm (S, H thiazole) - 1H at 5.85 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇) - 1H at 5.25 ppm (D, J=13 Hz, CH₂ OCO) - 1H at 5.15 ppm (D, J=4 Hz, H₆) - 1H at 4.91 ppm (D, J=13 Hz, CH₂ OCO) - 2H at 3.84 ppm (S, ArCH₂ S) - 2H at 3.68 ppm (AB, J_(AB) =17 Hz, CH₂ S) - 2H at 2.95 ppm (M, CH₂ --N⁺ H₃) - 2H at 2.51 ppm (M, CH₂ --CH₂ N⁺ H₃) - 6H at 1.38 ppm (2S, (CH₃)₂ --C) - .

NMR n° 25

1H at 9.55 ppm (D, J=9 Hz, NHCO) - 1H at 7.80 ppm (S.e., CH₂ NH⁺ H₃) - 1H at 6.70 ppm (S, H thiazole) - 1H at 5.76 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇) - 1H at 5.09 ppm (D, J=4 Hz, H₆) - 1 H at 4.95 and 1H at 4.55 ppm (D, J=13 Hz, CH₂ OCO) - 3H at 3.80 ppm (S, CH₃ ON) - 2H at 3.50 ppm (AB, J_(AB) =17 Hz, CH₂ S) - 2H at 2.60 ppm (M, CH₂ N⁺ H₃) - 1H at 2.25 ppm (M, H cyclohexane γ CH₂ N) - 9H between 0.8 and 2.0 ppm (M, H cyclohexane) - .

NMR n° 26

1H at 9.56 (D, J=9 Hz, CO NH) - 1H at 8.88 ppm (T, J=7 Hz, Ar CH₂ NH CO) - 3H at 8.00 ppm (S.e., N⁺ H₃) - 2H at 7.90 ppm (D, J=8 Hz, H aromatics ortho CO₂) - 2H at 7.37 ppm (D, J=8 Hz, H aromatique meta CO₂) - 1H at 6.70 ppm (S, H thiazole) - 1H at 5.77 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇) - 1H at 5.20 ppm (D, J=13 Hz, CH₂ OCO) - 1H at 5.13 ppm (D, J=4 Hz, H₆) - 1H at 4.90 ppm (D, J=13 Hz, CH₂ OCO) - 2H at 3.41 ppm (D, J=7 Hz, Ar CH₂ NH) - 3H at 3.80 ppm (S, CH₂ ON) - 4H at 3.55 ppm (M, CH₂ NH₃ ⁺ and CH₂ S) - .

NMR n° 27

1H at 9.56 (D, J=9 Hz, CO NH) - 1H at 8.85 ppm (T, J=7 Hz, Ar CH₂ NH CO) - 3H at 7.95 ppm (S.e., N⁺ H₃) - 2H at 7.91 ppm (D, J=8 Hz, H aromatics ortho CO₂) - 2H at 7.39 ppm (D, J=8 Hz, H aromatics meta CO₂) - 2H at 7.30 ppm (S.e., NH₂ thiazole) - 1H at 6.76 ppm (S, H thiazole) - 1H at 5.84 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇) - 1H at 5.27 ppm (D, J=13 Hz, CH₂ OCO) - 1H at 5.16 ppm (D, J=4 Hz, H₆) - 1H at 4.89 ppm (D, J=13 Hz, CH₂ OCO) - 2H at 4.40 ppm (D, J=7 Hz, ArCH₂ NHCO) - 4H at 3.60 ppm (M, CH₂ S and CH₂ N⁺ H₃) - 6H at 1.41 ppm (2S, (CH₃)₂ C) - .

NMR n° 28

1H at 9.40 ppm (D, J=9 Hz, CONH)-1H at 8.84 ppm (T, J=7 Hz, Ar CH₂ NH)-3H at 7.95 ppm (S.e., NH₃ ⁺)-2H at 7.85 ppm (M, H aromatics ortho CO₂)-2H at 7.51 ppm (M, H aromatics meta et para CO₂)-1H at 6.67 ppm (S, H thiazole)-1H at 5.84 ppm (D de D, J₁ =9 Hz J₂ =4 Hz, H₇)-1H at 5.25 ppm (D, J=13 Hz, CH₂ OCO)-1H at 5.17 ppm (D, J=4 Hz, H₆)-1H at 4.93 ppm (D, J=13 Hz, CH₂ OCO)-2H at 4.42 ppm (T, J=7 Hz, Ar CH₂ NH)-4H at 3.60 ppm (M, Ch₂ S and CH₂ NH₃)- 6H at 1.41 ppm (2S, (CH₃)₂ C)-.

NMR n° 29

1H at 9.56 ppm (D, J=9 Hz, CONH)-1H at 8.70 ppm and 1H at 8.42 ppm (S.e., N⁺ H₂ piperidine)-2H at 7.30 ppm (S.e., NH₂ thiazole)-1H at 6.65 ppm (S, H thiazole)-1H at 5.76 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇)-1H at 5.08 ppm (D, J=4 Hz H₆)-1H at 4.95 ppm and 1H at 4.71 ppm (D, J=13 Hz, CH₂ OCO)-3H at 3.79 ppm (S, CH₃ ON)-2H at 3.55 ppm (AB, J_(AB) =17 Hz, CH₂ S)-2H at 3.20 ppm (M, Hequatoriaux piperidine αNH)-2H 2.90 ppm (M, H axial piperidine αNH)-1H at 2.56 ppm (M, OCO <CH)-2H at 1.95 ppm (H equatorial piperidine βNH)-. 2H at 1.56 ppm (Haxial piperidine βNH) -.

NMR n° 30

1H at 9.58 ppm (D, J=9 Hz, CONH)-1H at 8.85 ppm (T, J=7 Hz, Ar CH₂ NHCO) 3H at 8.02 ppm (S.e., N⁺ H₃)-2H at 7.84 ppm (M, H aromatics ortho CO₂)-2H at 7.50 ppm (M, H aromatics meta and para CO₂)-1H at 6.71 ppm (S, H thiazole)-1H at 5.80 ppm (D de D, J₁ =9 Hz J₂ =4 Hz, H₇)-1H at 5.24 ppm (D, J=13 Hz, CH₂ OCO)-1H at 5.13 ppm (D, J=4 Hz, H₆) 1H at 4.92 ppm (D, J=13 Hz, CH₂ OCO)-2H at 4.37 ppm (D, J=7 Hz, Ar CH₂ NH)- 3H at 3.82 ppm (S, CH₃ ON)-4 H at 3.60 ppm (M, CH₂ S and CH₂ N⁺ H₃) -.

NMR n° 31

1H at 9.46 ppm (D, J=9 Hz, CONH)-2H at 7.86 ppm (M, H aromatics ortho CO₂)-3H at 7.80 ppm (S.e., N⁺ H₃)-1H at 7.55 ppm (D, J=8 Hz, H aromatic para CO₂)-1H at 7.50 ppm (T, J=8 Hz, H aromatic meta CO₂)-2H at 7.30 ppm (S.e., NH₂ thiazole)-1H at 6.70 ppm (S, H thiazole)-1H at 5.84 ppm (D de D, J₁ =9 Hz J₂ =4 Hz, H₇)-1H at 5.16 ppm (D, J=4 Hz, H₆)-1H at 5.25 ppm and 1H at 4.90 ppm (D, J=13 Hz, CH₂ OCO)-2H at 3.62 ppm (AB, J_(AB) =17 Hz, CH₂ S)-3H at 3.02 ppm (M, ##STR70## at 1.40 ppm (2S, (CH₃)₂ -C)-3H at 1.20 ppm (D, J=7 Hz, ##STR71## .

NMR n° 32

1H at 9.51 ppm (D, J=9 Hz, CONH)-1H at 7.80 ppm (S.e., N⁺ H₃)-2H at 7.25 ppm (S.e., NH₂ thiazole)-1H at 6.70 ppm (S, H thiazole)-1H at 5.84 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇)-1H at 5.17 ppm (D, J=4 Hz, H₆)-1H at 4.97 ppm et 1H at 4.60 ppm (D, J=13 Hz, CH₂ OCO)-1H at 3.56 ppm et 1H at 3.44 ppm (D, J=17 Hz, CH₂ S)-2H at 2.56 ppm (M, CH₂ N⁺ H₃)-5H at 2.40 ppm (M, ##STR72## and OCO--<CH)-6H at 1.90 ppm, 1H at 1.45 ppm 2H, at 1.25 ppm and 2H at 0.95 ppm (M, ##STR73## and CH₂ and CH cyclohexane).

NMR n° 33

1H at 9.60 ppm (D, J=9 Hz, CONH)-2H at 7.90 ppm (M, H aromatics ortho CO₂)-3H at 7.80 ppm (S.e., N⁺ H₃)-1H at 7.55 ppm (D, J=8 Hz, H aromatic para CO₂)-1H at 7.50 ppm (T, J=8 Hz, H aromatic meta CO₂)-2H at 7.36 ppm (S.e., NH₂ thiazole)-1H at 6.71 pp (S, Hthiazole)-1H at 5.79 ppm (D de D, J₁ =9 Hz J₂ =4 Hz, H₇)-1H at 5.11 ppm (D, J=4 Hz, H₆)-1H at 5.25 ppm 1H at 4.95 ppm (D, J=13 Hz, CH₂ OCO)-3H at 3.80 ppm (S, H₃ CON)-2H at 3.61 ppm (AB, J_(AB) =17 Hz, CH₂ S)-3H at 3.02 ppm (M, ##STR74## at 1.21 ppm (D, J=7 Hz, ##STR75##

NMR n° 34

1H at 9.60 ppm (D, J=9 Hz, NHCO)-3H at 8.25 ppm (S.e., N⁺ H₃)-1H at 8.05 ppm (S, Haromatic ortho CO₂ and ortho CH₂)-1H at 7.95 ppm (D, J=8 Hz, H aromatic ortho CO₂ and para CH₂)-1H at 7.70 ppm (D, J=8 Hz, H aromatic para CO₂)-1H at 7.55 ppm (T, J=8 Hz, H aromatic meta CO₂)-1H at 6.70 ppm (S, H thiazole)-1H at 5.75 ppm (D de D, J₁ =9 Hz J₂ =4 Hz, H₇)-1H at 5.20 ppm (D, J=13 Hz, CH₂ OCO)-1H at 5.10 ppm (D, J=4 Hz, H₆)-1H at 4.95 ppm (D, J=13 Hz, CH₂ OCO)- 2H at 4.10 ppm (M, CH₂ Ar)-3H at 3.80 ppm (S, CH₃ ON)-2H at 3.70 ppm (AB, J_(AB) =17 Hz, CH₂ S)-.

NMR n° 35

1H at 9.58 ppm (D, J=9 Hz, NHCO)-2H at 8.60 ppm (2 S.e., NH₂ ⁺ piperidinium)-2H at 7.40 ppm (S.e. NH₂ thiazole)-1H at 7.11 ppm (S, H thiazole)-1H at 5.75 ppm (D of D, J₁ =9 Hz, J₂ =4 Hz, H₇)-1H at 5.10 ppm (D, J=4 Hz, H₆)-1H at 5.00 ppm (2 D, J=13 Hz, CH₂ OCO)-1H at 4.75 ppm (2 D, J=13 Hz, CH₂ OCO)-3H at 3.80 ppm (S, NOCH₃)-2H at 3.50 ppm (AB, J_(AB) =17 Hz, CH₂ S)-5H between 3.45 and 2.6 ppm (M, CH₂ N et CO₂ H-<CH)-4H between 2.00 and 1.45 ppm (M, (CH₂)₂ -CH₂ N)-CH₂ N)-.

NMR n° 36

1H at 9.56 ppm (2 D, J=9 Hz, NHCO)-7.80 ppm (S.e., CH₂ NH₃ ⁺)-2H at 7.40 ppm (S.e., NH₂ thiazole)-1H at 6.72 ppm (S, H thiazole)-1H at 5.75 ppm (D of D, J₁ =9 Hz, J₂ =4 Hz, H₇)-1H at 5.09 ppm (D, J=4 Hz, H₆)-1H at 5.00 ppm (2 D, J=13 Hz, CH₂ OCO)-1H at 4.65 ppm (2 D, J=13 Hz, CH₂ OCO)-3H at 3.83 ppm (S, NOCH₃)-1H at 3.54 ppm (2 D, J=17 Hz, CH₂ S)-1H at 3.45 ppm (2 D, J=17 Hz, CH₂ S)-3H at 2.83 ppm (M, CH₂ NH₃ ⁺ et <CH-COOH)- 9H between 2.0 and 1.1 ppm (M, CH₂ cyclohexane and --CH--CH₂ NH₃ ⁺)-.

NMR n° 37

1H at 9.61 ppm (D, J=9 Hz, NHCO)-3H at 7.85 ppm (S.e., CH₂ NH₃ ⁺)-2H at 7.40 ppm (S.e., NH₂ thiazole)-1H at 6.71 ppm (S, H thiazole)-1H at 5.79 ppm (D of D, J₁ =9 Hz, J₂ =4 Hz, H₇)-1H at 5.09 ppm (D, J=4 Hz, H₆)-1H at 5.02 ppm (2 D, J=13 Hz, CH₂ OCO)-1H at 4.56 ppm (2 D, J=13 Hz, CH₂ OCO)-3H at 3.83 ppm (S, NOCH₃)-3H at 3.82 ppm (AB, J_(AB) =17 Hz, CH₂ S)-1H at 3.00 ppm et 1H at 2.87 ppm (2M, CH₂ NH₃ ⁺)-1H at 2.77 ppm ##STR76## at 1.12 ppm (D, J=7 Hz, ##STR77## .

NMR n° 38

1H at 9.62 ppm (D, J=9 Hz, CONH)-3H at 7.85 ppm (S.e., >CH--NH₃ ⁺)-2H at 7.40 ppm (S.e., NH₂ thiazole)-1H at 6.70 ppm (S, H thiazole)-1H at 5.76 ppm (D de D, J₁ =9 Hz, J₂ =4 Hz, H₇)-1H at 5.08 ppm (D, J=4 Hz, H₆)-1H at 4.95 ppm (D, J=13 Hz, CH₂ OCO)-1H at 4.69 ppm (D, J=13 Hz, CH₂ OCO)-3H at 3.50 ppm (AB, J_(AB) =17 Hz, --CH₂ S)-1H at 3.00 ppm (M, >CH--NH₃ ⁺)-1H at 2.50 ppm (M, >CH--COOH)-1H at 2.10 ppm, 3H at 1.85 ppm et 4H at 1.30 ppm (3M, CH₂ cyclohexane)-.

NMR n° 39

1H at 9.40 ppm (D, J=9 Hz, NHCO)-2H at 7.91 ppm (D, J=8 Hz, H aromatics ortho O-CO)-3H at 7.80 ppm (S.e., CH₂ NH₃ ⁺)-2H at 7.45 ppm (D, J=8 Hz, H aromatics meta O--CO)-2H at 7.40 ppm (S.e., NH₂ thiazole)-1H at 6.70 ppm (S, H thiazole)-1H at 5.81 (D de D, J₁ =9 Hz, J₂ =4 Hz, H₇)-1H at 5.23 ppm (D, J=13 Hz, CH₂ OCO)-2H at 3.85 ppm (S, ArCH₂ S)-3H at 3.81 ppm (S, NOCH₃)-2H at 3.70 ppm (AB, J_(AB) =17 Hz, CH₂ S)-2H at 2.95 ppm (M, CH₂ NH₃ ⁺)-2H at 2.55 ppm (T, J=7 Hz, S-CH₂ CH₂ NH₂)-.

NMR n° 40

1H at 10.55 ppm (S, ArNHCO)-1H at 9.61 ppm (D, J=9 Hz, CONH)-2H at 7.82 ppm (D, J=8 Hz, H aromatics ortho-OCO--)-3H at 7.77 ppm (S.e., CH₂ NH₃ ⁺)-2H at 7.60 ppm (D, J=8 Hz, H aromatics meta-OCO--)-2H at 7.35 ppm (S.e., NH₂ thiazole)-1H at 6.71 ppm (S, H thiazole)-1H at 5.78 ppm (D of D, J₁ =9 Hz, J₂ =4 Hz, H₇)-2H at 5.15 ppm (M, H₆ and CH₂ OCO)-1H at 4.96 ppm (D, J=13 Hz, CH₂ OCO)-3H at 3.80 ppm (S, NOCH₃)-2H at 3.60 ppm (AB, J_(AB) =17 Hz, CH₂ S)-2H at 3.60 ppm (M, CH₂ NH₃ ⁺)-2H at 2.70 ppm (T, J=7 Hz, CH₂ -CH₂ NH₃ ⁺)-.

NMR n° 41

1H at 9.60 ppm (D, J=9 Hz, CONH--)-2H at 8.60 ppm (S.e., NH₂ ⁺ piperidinium)-2H at 7.40 ppm (S.e., NH₂ thiazole)-1H at 6.76 ppm (S, H thiazole)-1H at 5.82 ppm (D of D, J₁ =9 Hz, J₂ =4 Hz, H₇)-1H at 5.15 ppm (D, J=4 Hz, H₆)-1H at 5.10 ppm (2D, J=13 Hz, CH₂ OCO)-1H at 4.76 ppm (2D, J=13 Hz, CH₂ OCO)-3H at 3.88 (N-OCH₃)-2H at 3.57 ppm (AB, J_(AB) =17 Hz, CH₂ S)-1H at 3.45 ppm (M, H αNH₂ ⁺)-1H at 3.26 ppm et 1H at 2.95 ppm (2M, CH₂ αNH₂ ⁺)- 2H at 2.70 ppm (M, OCO--CH₂)-6H between 1.3 and 2 ppm (M, CH₂ β et γ NH₂ ⁺)-.

NMR n° 42

1H at 9.70 ppm (D, J=9 Hz, CONH)-1H at 8.60 ppm and 1H at 8.25 ppm (2M, NH₂ ⁺ piperidinium)-2H at 7.40 ppm (S.e., NH₂ thiazole)-1H at 6.76 ppm (S, H thiazole)-1H at 5.82 ppm (D of D, J₁ =9 Hz, J₂ =4 Hz, H₇)-1H at 5.15 ppm (D, J=4 Hz, H₆)-1H at 5.02 ppm (D, J=13 Hz, CH₂ OCO)-1H at 4.74 ppm (D, J=13 Hz, CH₂ OCO)-3H at 3.87 ppm (S, NOCH₃)-2H at 3.57 ppm (AB, J_(AB) =17 Hz, CH₂ S)-2H at 3.25 ppm (M, H equatorial piperidiunm α NH₂ ⁺)-2H at 2.90 ppm (M, H axial piperidinium αNH₂ ⁺)- 2H at 2.35 ppm (D, J=7 Hz, OCOCH₂ --)-1H at 2.00 ppm (M, OCOCH₂ <CH)-2H at 1.80 ppm and 2H at 1.40 ppm (2M, CH₂ piperidium βNH₂ ⁺)-.

NMR n° 43

1H at 9.70 ppm (D, J=9 Hz, CONH)-2H at 9.00 ppm (S.e., ##STR78## at 8.05 ppm (D, J=8 Hz, H aromatics ortho OCO)-2H at 65 ppm (D, J=8 Hz, H aromatics meta OCO)-2H at 7.40 ppm (S.e., NH₂ thiazole)-1H at 6.80 ppm (S, H thiazole)-1H at 5.85 ppm (D of D, J₁ =9 Hz, J₂ =4 Hz, H₇)-1H at 5.30 ppm (D, J=13 Hz CH₂ OCO)-1H at 5.20 ppm (D, J=4 Hz, H₆)-1H at 5.00 ppm (D, J=13 Hz, CH₂ OCO)-2H at 4.27 ppm (M, ArCH₂ NH₂ ⁺ --)-3H at 3.90 ppm (S, NOCH₃)-2H at 3.75 ppm (AB, J_(AB) =17 Hz, CH₂ S)-1H at 3.40 ppm ##STR79## at 1.30 ppm (D, J=7 Hz, ##STR80##

NMR n° 44

1H at 9.20 ppm (D, J=9 Hz, CONH)-3H at 8.05 ppm (S.e., ArCH₂ N⁺ H₃)-2H at 7.40 ppm (S.e., NH₂ thiazole)-1H at 7.10 ppm (S, H aromatic)-1H at 6.70 ppm (S, H thiazole)-1H at 5.84 ppm (D of D, J₁ =9 Hz, J₂ =4 Hz, H₇)-2H at 5.20 ppm (M, H₆ and CH₂ OCO)-1H at 5.04 ppm (D, J=13 Hz, CH₂ OCO)-2H at 4.10 ppm (M, ArCH₂ N⁺ H₃)-3H at 3.80 ppm (S, NOCH₃)-2H at 3.60 ppm (AB, J_(AB) =17 Hz, CH₂ S)-3H at 1.40 ppm, 3H at 1.30 ppm and 3H at 1.20 ppm (3S, CH₃ Ar)-.

NMR n° 45

1H at 9.70 ppm (D, J=9 Hz, CONH)-3H at 8.15 ppm (S.e., NH₃ ⁺)-2H at 7.40 ppm (S.e., NH₂ thiazole)-2H at 7.40 ppm and 2H at 7.00 ppm (2D, J=8 Hz, H aromatics)-1H at 6.80 ppm (S, H thiazole)-1H at 5.82 ppm (D of D, J₁ =9 Hz, J₂ =4 Hz, H₇)-1H at 5.15 ppm (D, J=4 Hz, H₆)-1H at 5.12 ppm (D, J=13 Hz, CH₂ OCO)-2H at 4.86 ppm (S, CH₂ OAr)-1H at 4.82 ppm (D, J=13 Hz, CH₂ OCO)-2H at 4.00 ppm (M, ArCH₂ N⁺ H₃)-3H at 3.85 ppm (S, NOCH₃)-2H at 3.55 ppm (AB, J_(AB) =17 Hz, CH₂ S)-.

NMR n° 46

1H at 9.58 ppm (D, J=9 Hz, CONH)-3H at 7.90 ppm (S.e., ##STR81## 2H at 7.40 ppm (S.e., NH₂ thiazole)-1H at 6.70 ppm (S, H thiazole)-1H at 5.82 ppm (D of D, J₁ =9 Hz, J₂ =4 Hz, H₇ )-1H at 5.10 ppm (D, J=4 Hz, H₆)-1H at 5.05 ppm (D, J=13 Hz, CH₂ OCO)-1H at 4.70 ppm (D, J=13 Hz, CH₂ OCO)-3H at 3.80 ppm (S, N-OCH₃)-2H at 3.55 ppm (AB, J_(AB) =17 Hz, CH₂ S)-2H at 2.95 ppm (M, CH₂ N⁺ H₃)-6H at 1.16 ppm ##STR82##

NMR n° 47

1H at 9.00 ppm (D, J=9 Hz, CONH)-3H at 8.05 ppm (S.e., CH₂ N⁺ H₃)-2H at 8.00 ppm (D, J=8 Hz, H aromatics ortho OCO)-2H at 7.50 ppm (D, J=8 Hz, H aromatics meta OCO)-2H at 7.30 ppm (S.e., NH₂ thiazole)-1H at 6.71 ppm (S, H thiazole)-1H at 5.80 ppm (Dof D, J₁ =9 Hz, J₂ =4 Hz, H₇)-1H at 5.25 ppm (D, J=13 Hz, CH₂ OCO)-1H at 5.10 ppm (D, J=4 Hz, H₆)-1H at 4.95 ppm (D, J=13 Hz, CH₂ OCO)-3H at 3.82 ppm (S, NOCH₃)-2H at 3.66 ppm (AB, J_(AB) =17 Hz, CH₂ S)-2H at 3.55 ppm (S.e., CH₂ N.sup. + H₃)-3H at 3.23 ppm (S, ##STR83##

NMR n° 48

1H at 9.46 ppm (D, J=9 Hz CONH)-1H at 8.51 ppm (S, H thiazole ester)-3H at 7.90 ppm (S.e., CH₂ N⁺ H₃)-2H at 7.45 ppm (S.e., NH₂ thiazole)-1H at 6.69 ppm (s, H thiazole)-1H at 5.82 ppm (D de D, J₁ =9 Hz, J₂ =4 Hz, H₇)-2H at 5.20 ppm (M, H₆ and CH₂ OCO)-1H at 4.96 ppm (D, J=13 Hz, CH₂ OCO)-2H at 3.60 ppm (AB, J_(AB) =17 Hz, CH₂ S)-4H at 3.25 ppm (M, CH₂ --CH₂ NH⁺ ₃)-6H at 1.42 ppm (2S, ##STR84##

NMR n° 49

1H at 9.60 ppm (D, J=9 Hz, CONH)-1H at 8.50 ppm (S, H thiazole ester)-3H at 7.85 ppm (S.e., CH₂ N⁺ H₃)-2H at 7.30 ppm (S.e., NH₂ thiazole)-1H at 6.71 ppm (S, H thiazole)-1H at 5.78 ppm (D of D, J₁ =9 Hz, J₂ =4 Hz, H₇)-1H at 5.19 ppm (D, J=13 Hz, CH₂ OCO)-1H at 5.14 ppm (D, J=4 Hz, H₆)-1H at 4.92 ppm (D, J=13 Hz, CH₂ OCO)-3H at 3.81 ppm (S, NOCH₃)-2H at 3.61 ppm (AB, J_(AB) =17 Hz, CH₂ S)-4H at 3.26 ppm (M, CH₂ CH₂ N⁺ H₃)-.

NMR n° 50

1H at 9.46 ppm (D, J=9 Hz, CONH)-1H at 8.50 ppm (S, H thiazole ester)-3H at 7.80 ppm (S.e., CH₂ N⁺ H₃)-2H at 7.40 ppm (S.e., NH₂ thiazole)-1H at 6.68 ppm (S, H thiazole)-1H at 5.80 ppm (D of D, J₁ =9 Hz, J₂ =4 Hz, H₇)-2H at 5.20 ppm (M, H₆ and CH₂ OCO)-1H at 4.86 ppm (D, J=13 Hz, CH₂ OCO)-2H at 3.66 ppm (AB, J_(AB) =17 Hz, CH₂ S)-2H at 3.00 ppm (T, J=7 Hz, CH₂ CH₂ CH₂ N⁺ H₃)-2H at 2.84 ppm (M, --CH₂ N⁺ H₃)-2H at 1.96 ppm (M, CH₂ CH₂ CH₂ N⁺ H₃ )-6H at 1.36 ppm (2S, ##STR85##

NMR n° 51

1H at 9.46 ppm (D, J=9 Hz, CONH)-1H at 8.50 ppm (S, H thiazole ester)-3H at 7.80 ppm (S.e., CH₂ N⁺ H₃)-2H at 7.40 ppm (S.e., NH₂ thiazole)-1H at 6.68 ppm (S, H thiazole)-1H at 5.80 ppm (D of D, J₁ =9 Hz, J₂ =4 Hz, H₇)-2H at 5.20 ppm (M, H₆ and CH₂ OCO)-1H at 4.96 ppm (D, J=13 Hz, CH₂ OCO)-3H at 3.81 ppm (S, NOCH₃)-2H at 3.66 ppm (AB, J_(AB) =17 Hz, CH₂ S)-2H at 3.08 ppm (T, J=7 Hz, --CH₂ CH₂ CH₂ N⁺ H₃)-2H at 2.84 ppm (M, CH₂ N⁺ H₃)-2H at 1.96 ppm (M, CH₂ CH₂ CH₂ N⁺ H₃)-.

NMR n° 52

1H at 9.60 ppm (D, J=9 Hz, CONH)-1H at 8.60 ppm (S, H thiazole ester)-3H at 8.50 ppm (S.e., CH₂ N⁺ H₃)-2H at 7.40 ppm (S.e., NH₂ thiazole)-1H at 6.70 ppm (S, H thiazole)-1H at 5.80 ppm (D of D, J₁ =9 Hz, J₂ =4 Hz, H₇)-2H at 5.15 ppm (M, H₆ and CH₂ OCO)-1H at 4.96 ppm (D, J=13 Hz, CH₂ OCO)-2H at 4.45 ppm (S.e., CH₂ N⁺ H₃)-3H at 3.78 ppm (S, NOCH₃)-2H at 3.57 ppm (AB, J_(AB) =17 Hz, CH₂ S)-.

NMR n° 53

1H at 9.70 ppm (D, J=9 Hz, CONH)-1H 8.70 ppm and 1H at 8.40 ppm (2M, N⁺ H₂ piperidinium)-2H at 7.80 ppm (S.e., NH₂ thiazole)-1H at 6.80 ppm (S, H thiazole)-1H at 5.85 ppm (D of D, J₁ =9 Hz, J₂ =4 Hz, H₇)-1H at 5.20 ppm (D, J=4 Hz, H₆)-1H at 5.00 ppm (D, J=13 Hz, CH₂ OCO)-1H at 4.72 ppm (D, J=13 Hz, CH₂ OCO)-2H at 3.90 ppm (D, J=7 Hz, NOCH₂ --)-2H at 3.55 ppm (AB, J_(AB) =17 Hz, CH₂ S)-2H at 3.25 ppm (M, H equatorial α N⁺ H₂ piperidinium)-2H at 2.90 ppm (M, H axial N⁺ H₂ piperidinium)-2H at 2.35 ppm (D, J=7 Hz, OCOCH₂)-3H at 2.00 ppm and 3H at 1.20 ppm (M, CH₂ βN⁺ H₂, OCOCH₂ --<CH et CH cyclopropyl)-2H at 0.50 ppm and 2H at 0.30 ppm (2M, CH₂ cyclopropane)-.

NMR n° 54

1H at 9.55 ppm (D, J=9 Hz, CONH)-3H at 7.70 ppm (S.e., CH₂ N⁺ H₃)-2H at 7.25 ppm (S.e., NH₂ thiazole)-1H at 6.72 ppm (S, H thiazole)-1H at 5.75 ppm (D of D, J₁ =9 Hz, J₂ =4 Hz, H₇)-1H at 5.08 ppm (D, J=4 Hz, H₆)-1H at 4.95 ppm (D, J=13 Hz, CH₂ OCO)-1H at 4.66 ppm (D, J=13 Hz, CH₂ OCO)-3H at 3.81 ppm (S, NOCH₃)-2H at 3.49 ppm (AB, J_(AB) =17 Hz, CH₂ S)-2H at 2.70 ppm (M, CH₂ N⁺ H₃)-2H at 2.30 ppm (T, J=7 Hz, CH₂ --(CH₂)₄ NH₂)-4H at 1.50 ppm (M, --CH₂ --CH₂ CH₂ --CH₂ --CH₂ N⁺ H₃)-2H at 1.20 ppm (M, --(CH₂)₂ --CH₂ --(CH₂)₂ N⁺ H₃)-.

NMR n° 55

1H at 9.62 ppm(D, J=9 Hz, CONH)-3H at 7.80 ppm (S.e., CH₂ N⁺ H₃)-2H at 7.55 ppm (S.e., NH₂ thiazole)-1H at 6.76 ppm (S, H thiazole)-1H at 5.80 ppm (D of D, J₁ =9 Hz, J₂ =4 Hz, H₇)-1H at 5.15 ppm (D, J=4 Hz, H₆)-1H at 5.10 ppm (D, J=13 Hz, CH₂ OCO)-1H at 4.70 ppm (D, J=13 Hz, CH₂ OCO)-3H at 3.85 ppm (S, N-OCH₃)-2H at 3.52 ppm (AB, J_(AB) =17 Hz, CH₂ S)-2H at 2.80 ppm (M, CH₂ N⁺ H₃)-2H at 2.35 ppm (T, J=7 Hz, OCOCH₂)-4H at 1.51 ppm and 6H at 1.26 ppm (2M, OCOCH₂ (CH₂)₅ --CH₂ N⁺ H₃)-.

NMR n° 56

1H at 9.56 ppm (D, J=9 Hz, CONH)-2H at 8.30 and 8.55 ppm (2M, N⁺ H₂ piperidinium)-2H at 7.40 ppm (S.e., NH₂ thiazole)-1H at 6.69 pm (S, H thiazole)-1H at 5.74 ppm (D of D, J₁ =9 Hz, J₂ =4 Hz, H₇)-1H at 5.10 ppm (D, J=4 Hz, H₆)-1H at 4.96 ppm (2D, J=13 Hz, CH₂ OCO)-1H at 4.66 ppm (D, J=13 Hz, CH₂ OCO)-3H at 3.80 ppm (S, NOCH₃)-2H at 3.49 ppm (AB, J_(AB) =17 Hz, CH₂ S)-2H at 3.15 ppm (M, H equatorital αN⁺ H₂ piperidinium)-1H at 2.75 ppm et 1H at 2.55 ppm (2M, H axial αN⁺ H₂ piperidinium)-2H at 2.36 ppm (T, J=7 Hz, OCOCH₂ --)-7H between 1 and 2 ppm (M, OCOCH₂ CH₂ - and 5H piperidinium)-.

NMR n° 57

1H at 9.45 ppm (D, J=9 Hz, CONH)-1H at 8.55 ppm and 1H at 8.40 ppm (2M, N⁺ H₂ piperidinium)-2H at 7.40 ppm(S.e., NH₂ thiazole)-1H at 6.69 ppm (S, H thiazole)-1H at 5.84 ppm (D of D, J₁ =9 Hz, J₂ =4 Hz, H₇)-1H at 5.13 ppm (D, J=4 Hz, H₆)-1H at 4.97 ppm (2D, J=13 Hz, CH₂ OCO)-1H at 4.66 ppm (D, J=13 Hz, CH₂ OCO)-2H at 3.51 ppm (AB, J_(AB) =17 Hz, CH₂ S)-2H at 3.16 ppm (M, H equatoriaux αN⁺ H₂ piperidinium)-1H at 2.75 ppm and 1H at 2.55 ppm (2M, H axial αN⁺ H₂ piperidinium)-2H at 2.36 ppm (T, J=7 Hz, OCOCH₂ --)-6H at 1.42 ppm (2S, ##STR86## between 1 and 2 ppm (M, OCOCH₂ CH₂, 5H piperidinium)-.

NMR n° 58

1H at 9.60 ppm (D, J=9 Hz, CONH)-1H at 8.55 ppm et 1H at 8.26 ppm (2 M.e., N⁺ H₂ piperidinium)-2H at 7.50 ppm (S.e., NH₂ thiazole)-1H at 6.70 ppm (S, H thiazole)-1H at 5.75 ppm (D of D, J₁ =9 Hz, J₂ =4 Hz, H₇)-1H at 5.10 ppm (D, J=4 Hz, H₆)-1H at 4.96 ppm (D, J=13 Hz, CH₂ OCO)-1H at 4.66 ppm (D, J=13 Hz, CH₂ OCO)-3H at 3.82 ppm (s, NOCH₃)-2H at 3.50 ppm (AB, J_(AB) =17 Hz, CH₂ S)-2H at 3.20 ppm (M, H equatorial αN⁺ H₂ piperidinium)-2H at 2.80 ppm (M, H axial αN⁺ H.sub. 2 piperidinium)-2H at 2.38 ppm (T, J=7 Hz, OCOCH₂)-2H at 1.70, 3H at 1.48 et 2H at 1.20 ppm (3M, CH₂ βN⁺ H₂ piperidinium, --<CHpiperidinium et OCOCH₂ CH₂)-.

NMR n° 59

1H at 9.45 ppm (D, J=9 Hz, CONH)-1H at 8.50 ppm et 1H at 8.20 ppm (2 M.e., N⁺ H₂ piperidinium)-2H at 7.50 ppm (S.e., NH₂ thiazole)-1H at 6.71 ppm (S, H thiazole)-1H at 5.84 ppm (D of D, J₁ =9 Hz, J₂ =4 Hz, H₇)-1H at 5.11 ppm (D, J=4 Hz, H₆)-1H at 4.96 ppm (D, J=13 Hz, CH₂ OCO)-1H at 4.67 ppm (D, J=13 Hz, CH₂ OCO)-2H at 3.52 ppm (AB, J_(AB) =17 Hz, CH₂ S)-2H at 3.24 ppm (M, H equatorial αN⁺ H₂ piperidinium)-2H at 2.77 ppm (M, H axial αN⁺ H₂ piperidinium)-2H at 2.42 ppm (T, J= 7 Hz, OCOCH₂ --)-2H at 1.70, 3H at 1.40 and 2H at 1.20 ppm (3M, CH₂ βN⁺ H₂ piperidinium, --<CH² piperidinium and OCOCH₂ CH₂)-6H at 1.42 ppm ##STR87##

NMR n° 60

1H at 9.47 ppm (D, J=9 Hz, CONH)-2H at 8.80 ppm (M, N⁺ H₂ decahydroquinoleinium)-2 H at 7.60 ppm (S.e., NH₂ thiazole)-1H at 6.71 ppm (S, H thiazole)-1H at 5.84 ppm (D of D, J₁ =9 Hz, J₂ =4 Hz, H₇)-1H at 5.12 ppm (D, J=4 Hz, H₆)-1H at 5.06 ppm (2D, J=13 Hz, CH₂ OCO)-1H at 4.72 ppm (D, J=13 Hz, CH₂ OCO)-2H at 3.55 ppm (AB, J_(AB) =17 Hz, CH₂ S)-1H at 3.40 ppm (M, HαN⁺ H₂ cycle junction)-1H at 3.20 ppm (M, H equatorial αN⁺ H₂ decahydroquinoleinium)-1H at 3.00 ppm (M, H axial αN⁺ H₂ decahydroquinoleinium)- 1H at 2.80 ppm (M, OCO--<CH)-6H at 1.42 ppm (2S, ##STR88## between 1 and 2.05 ppm (M, H decahydroquinoleinium)-.

NMR n° 61

1H at 9.60 ppm (D, J=9 Hz, CONH)-1H at 8.80 ppm (T, J=7 Hz, ArCONH)-2H at 8.00 ppm (D, J=8 Hz, H aromatic)-2H at 7.90 ppm (D, J=8 Hz, H aromatic)-3H at 7.75 ppm (S.e., CH₂ N⁺ H₃)-2H at 7.30 ppm (S.e., NH₂ thiazole)-1H at 6.71 ppm (S, H thiazole)-1H at 5.79 ppm (D of D, J₁ =9 Hz, J₂ =4 Hz, H₇)-1H at 5.24 ppm (D, J=13 Hz, CH₂ OCO)-1H at 5.12 ppm (D, J=4 Hz, H₆)-1H at 4.94 ppm (D, J=13 Hz, CH₂ OCO)-3H at 3.80 ppm (S, NOCH₃)-2H at 3.68 ppm (AB, J_(AB) =17 hz, CH₂ S)-2H at 3.50 ppm (M, CH₂ N⁺ H₃)-2H at 2.95 ppm (M, CH₂ CH₂ N⁺ H₃)-.

NMR n° 62

1H at 9.45 pp (D, J=9 Hz, CONH)-1H at 8.80 ppm (T, J=7 Hz, ArCONH)-2H at 8.00 ppm (D, J=8 Hz, H aromatic)-2H at 7.90 ppm (D, J=8 Hz, H aromatics)-3H at 7.80 ppm (S.e., CH₂ N⁺ H₃)-2H at 7.40 ppm (S.e., NH₂ thiazole)-1H at 6.70 ppm (S, H thiazole)-1H at 5.84 ppm (D of D, J₁ =9 Hz, J₂ =4 Hz, H₇)-1H at 5.25 ppm (D, J=13 Hz, CH₂ OCO)-1H at 5.15 ppm (D, J=4 Hz, H₆)-1H at 4.95 ppm (D, J=13 Hz, CH₂ OCO)-2H at 3.69 ppm (AB, J_(AB) =17 Hz, CH₂ S)-2H at 3.50 ppm (M, CH₂ N⁺ H₃)-2H at 2.98 ppm (M, CH₂ --CH₂ N⁺ H₃)-6H at 1.41 ppm (2S, ##STR89##

EXAMPLE 64 7-[2-(2-amino 4-thiazolyl) 2-(2-carboxy 2-propyl oxyimino) acetamido]3-[(2-methyl 4-aminomethyl benzoyl)thiomethyl] 3-cepheme 4-carboxylic acide bis trifluoracetate syn isomer (SR 42943) (I) R₁ =R₂ =CH₃ R₃ =COOH X=S n=0 ##STR90##

(a) 2-methyl 4-tertiobutoxycarbonylaminomethyl thiobenzoic acid.

2.65 g of 2-methyl 4-tertiobutoxycarbonylaminomethyl thiobenzoic acid and 1.4 ml of triethylamine are dissolved in 60 ml of methylene chloride. The solution is cooled to 4° C. then 1.3 ml of isobutyl chloroformiate are added and the mixture is stirred for 15 minutes. Keeping the temperature to 4° C., a current of hydrogen sulfide is bubbled through the solution and 1.5 ml of triethylamine are added. After 15 minutes, the current of hydrogen sulfide is stopped and stirring continues for 15 minutes, still at 4° C. The solvent is evaporated in vacuo and the residual is taken up in methylene chloride and the sulfate buffer pH2. The organic phase is separated and the aqueous phase is re-extracted with methylene chloride. The organic phases are re-grouped, dried over magnesium sulfate and evaporated to dryness. The residual is taken up in 40 ml of acetone and the solution is used as is in the next step.

(b) 7-[2-(2-tritylamino 4-thiazolyl) 2-(2-tertiobutoxycarbonyl 2-propyl oxyimino acetamido] 3-[(2-methyl 4-tertiobutoxycarbonylaminomethyl benzoyl) thiomethyl] 3-cepheme 4-carboxylate of teriobutyl 1 β-S-oxide syn isomer.

A mixture of 2 g of 7-[2-(2-tritylamino 4-thiazolyl) 2-(2-tertiobutoxycarbonyl 2-propyl oxyimino) acetamido] 3-bromomethyl 3-cepheme carboxylate of 4-tertiobutyl 1μ-S-oxide syn isomer, 1 g of sodium iodide and 3 g of potassium bicarbonate in 21 ml of the acetonic thioacide solution prepared above, is stirred for 3 hours at ambient temperature.

The solvent is evaporated to dryness and the residual is taken up in water and methylene chloride. The organic phase is separated, dried over magnesium sulfate and evaporated to dryness.

The product obtained is chromatographed on a column of silica H. The expected product is obtained by eluting with the mixture methylene chloride-methanol: 100-0.7 (vol/vol).

(c) 7-[2-(2-tritylamino 4-thiazolyl) 2-(2-tertiobutoxycarbonyl 2-propyl oxyimino) acetamido] 3-[(2-methyl 4-tertiobutoxycarbonylaminomethyl benzoyl) thiomethyl] 3-cepheme 4-carboxylate of tertiobutyl syn isomer.

Reduction of the S-oxide is carried out with phosphorous tribromide, as indicated in Example 1b.

The resulting product is purified by chromatography on silica H by eluting with the mixture methylene chloride-ethyl acetate 95-5 (vol/vol).

(d) SR 42943.

Using the product obtained above, deprotection is carried out as indicated in Example 1c.

The expected product is isolated in the same way.

NMR Spectrum

1H at 9.40 ppm (D, J=9 Hz, CO NH)-3H at 8.20 ppm (S.e., Ar CH₂ N⁺ H₃)-1H at 7.80 ppm (D, J=8 Hz, H aromatic ortho OCS)-2H at 7.40 ppm (M, H aromatics meta OCS)-1H at 6.70 ppm (S, H thiazole)-1H at 5.80 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇)-1H at 5.10 ppm (D, J=4 Hz, H₆)-1H at 4.20 ppm (D, J=13 Hz, CH₂ SCO)-2H at 4.00 ppm (M, Ar CH₂ N⁺ H₃)-1H at 3.95 ppm (D, J=13 Hz, CH₂ SCO)-1H at 3.75 ppm et 1H at 3.40 ppm (D, J=17 Hz, CH₂ S)-1H at 2.37 ppm (S, Ar CH₃)-6H at 1.42 ppm (2S, (CH₃)₂ --C)-.

EXAMPLES 65 to 84

The compounds according to the invention are prepared according to the method used in Example 64, they are isolated in trifluoracetate form, and described in Table II, hereafter.

                                      TABLE II                                     __________________________________________________________________________      ##STR91##                                                                                                        IR Spectrum                                                                    Intermediate 3                                                                         NMR                                 SR No.                                                                             n R.sub.1                                                                           R.sub.2                                                                           R.sub.3                                                                            B                  γCO cm.sup.-1                                                                    Spectrum                            __________________________________________________________________________     42 887                                                                             0 H  H  H                                                                                   ##STR92##         1790-1710 1685 (CH.sub.2 Cl.sub.2)                                                     63                                  42 936                                                                             0 H  H  H                                                                                   ##STR93##         1785-1700 1650                                                                         64                                  42 878                                                                             0 CH.sub.3                                                                          CH.sub.3                                                                          COOH                                                                                ##STR94##         1790-1720 1685                                                                         65                                  42 935                                                                             0 CH.sub.3                                                                          CH.sub.3                                                                          COOH                                                                                ##STR95##         1790-1715 1655 (CH.sub.2 Cl.sub.2)                                                     66                                  42 944                                                                             0 CH.sub.3                                                                          CH.sub.3                                                                          COOH                                                                                ##STR96##         1790-1720                                                                              67                                  42 967                                                                             0 H  H  H                                                                                   ##STR97##         1785-1710                                                                              68                                  42 969                                                                             0 H  H  H                                                                                   ##STR98##         1785-1710 1675                                                                         69                                  42 973                                                                             0 H  H  H                                                                                   ##STR99##         1785-1715 1670                                                                         70                                  42 975                                                                             0 H  H  H                                                                                   ##STR100##        1785-1715 1670                                                                         71                                  43 014                                                                             0 CH.sub.3                                                                          CH.sub.3                                                                          COOH                                                                                ##STR101##        1790-1715                                                                              72                                  43 015                                                                             0 CH.sub.3                                                                          CH.sub.3                                                                          COOH                                                                                ##STR102##        1790-1715 1685                                                                         73                                  43 025                                                                             0 H  H  H                                                                                   ##STR103##        1790-1710 1675                                                                         74                                  43 031                                                                             0 H  H  H                                                                                   ##STR104##        1785-1710                                                                              75                                  43 027                                                                             0 H  H  H                                                                                   ##STR105##        1790-1685                                                                              76                                  43 191                                                                             0 H  H  H                                                                                   ##STR106##        1785-1710 1675                                                                         77                                  43 192                                                                             0 CH.sub.3                                                                          CH.sub.3                                                                          COOH                                                                                ##STR107##        1790-1700                                                                              78                                  43 193                                                                             0 CH.sub.3                                                                          CH.sub.3                                                                          COOH                                                                                ##STR108##        1790-1720                                                                              79                                  43 234                                                                             1 H  H  H                                                                                   ##STR109##                80                                  43 235                                                                             1 CH.sub.3                                                                          CH.sub.3                                                                          COOH                                                                                ##STR110##                81                                  43 525                                                                             0 H  H                                                                                  ##STR111##                                                                         ##STR112##        1785-1680                                                                              82                                  __________________________________________________________________________

NMR n° 63

1H at 12.73 ppm (S, thiazole-NH CO)-4H at 8.30 ppm (S.e., CH₂ NH⁺ ₃ and NH CO)-1H at 8.10 ppm (S, H thiazole thioester)-2H at 7.25 ppm (S.e., NH₂ thiazole)-1H at 6.69 ppm (S, H thiazole amine)-1H at 5.70 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇)-1H at 5.07 ppm (D, J=4 Hz, H₆)-1H at 4.20 ppm (D, J=13 Hz, CH₂ SCO)-3H at 3.90 ppm (M, CH₂ SCO and NHCOCH₂ N⁺)-3H at 3.80 ppm (S, CH₃ ON)-1H at 3.67 ppm and 1H at 3.34 ppm (D, J=17 Hz, CH₂ S)-.

NMR n° 64

1H at 9.55 ppm (D, J=9 Hz, NHCO)-3H at 8.00 ppm (S.e., N⁺ H₃)-2H at 7.30 ppm (S.e., NH₂ thiazole)-1H at 6.71 ppm (S, H thiazole). 1H at 5.73 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇)-1H at 5.10 ppm (D, J=4 Hz, H₆)-1H at 4.30 ppm (M, H piperidine α N equatorial)-4H at 3.90 ppm (M, CH₂ SCO et COCH₂ N⁺ H₃)-3H at 3.80 ppm (S, CH₃ ON)-2H at 3.60 ppm (M, H piperidine α N equatorial and CH₂ S)-1H at 3.25 ppm (D, J=17 Hz, CH₂ S)-1H at 3.05 ppm (M, H piperidine α N axial)-1H at 2.90 ppm (M, S--CO--<CH)-1H at 2.75 ppm (M, H piperidine α N axial)-4H between 1.3 and 2 ppm (M, H piperidine β N)-.

NMR n° 65

1H at 12.69 ppm (S, thiazole-NH-CO)-1H at 9.42 ppm (D, J=9 Hz, CO NH)-3H at 8.30 ppm (S.e., N⁺ H₃)-1H at 8.10 ppm (S, H thiazole thioester)-2H at 7.30 ppm (S.e., NH₂ thiazole)-1H at 6.70 ppm (S, H thiazole amine)-1H at 5.76 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇)-1H at 5.11 ppm (D, J=4 Hz, H₆)-1H at 4.25 ppm (D, J=13 Hz, CH₂ SCO)-2H at 3.87 ppm (M, COCH₂ N⁺)-1H at 3.83 ppm (D, J=13 Hz, CH₂ SCO)-1H at 3.67 ppm and 1H at 3.34 ppm (D, J=17 Hz, CH₂ S)-6H at 1.40 ppm (2 S, (CH₃)₂ C)-.

NMR n° 66

1H at 9.42 ppm (D, J=9 Hz, NHCO)-3H at 8.00 ppm (S.e., N⁺ H₃)-2H at 7.30 ppm (S.e., NH₂ thiazole)-1H at 6.66 ppm (S, H thiazole)-1H at 5.75 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇)-1H at 5.07 ppm (D, J=4 Hz, H₆)-1H at 4.20 ppm (M, H piperidine α N equatorial)-1H at 4.00 ppm (D, J=13 Hz, CH₂ SCO)-2H at 3.80 ppm (M, CO--CH₂ N⁺)-1H at 3.70 ppm (D, J=13 Hz, CH₂ SCO)-2H at 3.60 ppm (M, H piperidine α N equatorial and CH₂ S)-2h at 3.27 ppm (D, J=17 Hz, CH₂ S)-1H at 3.00 ppm (M, H piperidine α N axial)-1H at 2.90 ppm (M, S--CO <H)-1H at 2.75 ppm (M, H piperidine α N axial)-4H between 1.5 and 2 ppm (M, H piperidine β N)-6H at 1.40 ppm (2S, (CH₃)₂ C)-.

NMR n° 67

1H at 9.40 ppm (D, J329 Hz, NHCO)-1H at 8.85 ppm (T, J=7 Hz, Ar CH₂ NH CO)-3H at 8.00 ppm (S.e, N⁺ H₃)-2H at 7.81 ppm (M, H aromatics ortho COS)-2H at 7.50 ppm (M, H aromatics meta, para COS)-1H at 6.66 ppm (S, H thiazole)-1H at 5.80 ppm (D of D, J₁ =13 Hz J₂ =4 Hz, H₇)-1H at 5.10 ppm (D, J=4 Hz, H₆)-2H at 4.39 ppm (D, J=7 Hz, Ar CH₂ NH CO)-1H at 4.27 ppm and 1H at 3.94 ppm (D, J=13 Hz, CH₂ SCO)-1H at 3.66 ppm (D, J=17 Hz, CH₂ S)-2H at 3.55 ppm (M, CH₂ NHCO)-1H at 3.37 ppm (D, J=17 Hz, CH₂ S)-6H at 1.40 ppm (2S, (CH₃)₂ C)-.

NMR n° 68

1H at 9.54 ppm (D, J=9 Hz, NHCO)-3H at 8.24 ppm (S.e., Ar CH₂ N⁺ H₃)-1H at 7.77 ppm (D, J=8 Hz, H aromatic ortho COS)-2H at 7.39 ppm (M, H aromatics meta COS)-2H at 7.27 ppm (S.e., NH₂ thiazole)-1H at 6.71 ppm (S, H thiazole)-1H at 5.75 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇)-1H at 5.09 ppm (D, J=4 Hz, H₆)-1H at 4.21 ppm (D, J=13 Hz, CH₂ SCO)-2H at 4.03 ppm (M, Ar CH₂ N⁺)-1H at 3.92 ppm (D, J=13 Hz, CH₂ SCO)-3H at 3.79 ppm (S, CH₃ ON)-1H at 3.71 ppm at 1H at 3.37 ppm (D, J=17 Hz, CH₂ S)-3H at 2.37 ppm (S, CH₃ -Ar)-.

NMR n° 69

1H at 9.53 ppm (D, J=9 Hz, NHCO)-1H at 8.57 ppm (S, H thiazole ester)-3H at 8.55 ppm (S.e., CH₂ N⁺ H₃)-2H at 7.30 ppm (S.e, NH₂ thiazole)-1H at 6.71 ppm (S, H thiazole amine)-1H at 5.71 ppm (D, J₁ =9 Hz J₂ =4 Hz, H₇)-1H at 5.09 ppm (D, J=4 Hz, H₆)-2H at 4.45 ppm (S.e., thiazole-CH₂ N⁺ H₃)-1H at 4.21 ppm and 1H at 3.89 ppm (D, J=13 Hz, CH₂ SCO)-3H at 3.79 ppm (S, CH₃ ON)-1H at 3.67 ppm and 1H at 3.39 ppm (D, J=17 Hz, CH₂ S)-.

NMR n° 70

1H at 9.52 ppm (D, J=9 Hz, NHCO)-1H at 8.90 ppm (T, J=7 Hz, Ar CH₂ NH CO)-3H at 8.00 ppm (S.e., N⁺ H₃)-2H at 7.80 ppm (M, H aromatics ortho COS)-2H at 7.53 ppm (M, H aromatics meta and para COS)-2H at 7.30 ppm (S.e., NH₂ thiazole)-1H at 6.68 ppm (S, H thiazole)-1H at 5.69 ppm (D de D, J₁ =9 Hz J₂ =4 Hz, H₇)-1H at 5.08 ppm (D, J=4 Hz, H₆)-1H at 4.39 ppm (D, J=7 Hz, Ar CH₂ NH)-1H at 4.27 ppm and 1H at 3.95 ppm (D, J=13 Hz, CH₂ SCO)-3H at 3.79 ppm (S, CH₃ ON)-1 H at 3.66 ppm (D, J=17 Hz, CH₂ S)-2H at 3.55 ppm (M, NHCOCH₂ N)-1H at 3.34 ppm (D, J=17 Hz, CH₂ S)-.

NMR n° 71

1H at 9.55 ppm (D, J=9 Hz, NHCO)-1H at 8.89 ppm (T, J=7 Hz, Ar CH₂ NHCO)-3H at 8.02 ppm (S.e., N⁺ H₃)-2H at 7.83 ppm (D, J=8 Hz, H aromatics ortho COS)-2H at 7.40 ppm (D, J=8 Hz, H aromatics meta COS)-2H 7.28 ppm (S.e., NH₂ thiazole)-1H 6.68 ppm (S, H thiazole)-1H at 5.71 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇)-1H at 5.11 ppm (D, J=4 Hz, H₆)-2H at 4.39 ppm (D, J=7 Hz, Ar CH₂ NH)-1H at 4.27 ppm and 1H at 3.95 ppm (D, J=13 Hz, CH₂ SCO)-3H at 3.79 ppm (S, CH₃ ON)-1H at 3.78 ppm (D, J=17 Hz, CH₂ S)-2H at 3.63 ppm (M, COCO₂ N⁺)-1H at 3.34 ppm (D, J=17 Hz, CH₂ S)-.

NMR n° 72

1H at 9.40 ppm (D, J=9 Hz, CO NH)-5H at 7.80 ppm (M, CH₂ N⁺ H₃ and H aromatic ortho COS)-1H at 7.56 ppm (D, J=8 Hz, H aromatic para COS)-1H at 7.50 ppm (T, J=8 Hz, H aromatic meta COS)-2H at 7.23 ppm (S.e., NH₂ thiazole)-1H at 6.68 ppm (S, H thiazole)-1H at 5.75 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇)-1H at 5.10 ppm (D, J=4 Hz, H₆)-1H at 4.28 ppm and 1H at 3.94 ppm (D, J=13 Hz, CH₂ SCO)-1H at 3.69 ppm and 1H at 3.36 ppm (D, J=17 Hz, CH₂ S)-3H at 3.00 ppm (M, ##STR113## at 1.40 ppm (2S, (CH₃)₂ C)-2H at 1.22 ppm (D, J=7 Hz, ##STR114##

NMR n° 73

1H at 12.70 ppm (S, thiazole NHCO)-1H at 9.45 ppm (D, J=9 Hz, NHCO)-1H at 8.05 ppm (S, H thiazole ester)-3H at 7.80 ppm (S.e., N⁺ H₃)-2H at 7.36 ppm (S.e., NH₂ thiazole)-1H at 6.69 ppm (S, H thiazole amine)-1H at 5.70 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇)-1H at 5.07 ppm (D, J=4 Hz, H₆)-1H at 4.24 ppm and 1H at 3.80 ppm (D, J=13 Hz, CH₂ SCO)-1H at 3.66 ppm and 1H at 3.40 ppm (D, J=17 Hz, CH₂ S)-2H at 3.05 ppm (M, CH₂ N⁺ H₃)-2H at 2.80 ppm (M, CH₂ CH₂ N⁺ H₃)-6H at 1.40 ppm (2S, (CH₃)₂ C)-.

NMR n° 74

1H at 12.60 ppm (S, thiazole NHCO)-1H at 9.55 ppm (D, J=9 Hz, NHCO-1H at 8.05 ppm (s, H thiazole ester)-3H at 7.83 ppm (S.e., NH₃ ⁺)-2H at 7.32 ppm (S.e., NH₂ thiazole)-1H at 6.71 ppm (S, H thiazole amine)-1H at 5.70 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇)-1H at 5.07 ppm (D, J=4 Hz, H₆)-1H at 4.25 ppm and 1H at 3.84 ppm (D, J=13 Hz, CH₂ SCO)-3H at 3.82 ppm (S, CH₃ ON)-1H at 3.65 ppm and 1H at 3.31 ppm (D, J=17 Hz, CH₂ S)-2H at 3.06 ppm (M, CH₂ N⁺ H₃)-2H at 2.80 ppm (M, CO--CH₂ CH₂ ⁺ N)-.

NMR n° 75

1H at 9.53 ppm (D, J=9 Hz, NHCO)-5H at 7.85 ppm (M, N⁺ H₃ and H aromatic ortho COS)-1H at 7.55 ppm (D, J=8 Hz, H aromatic para COS)-1H at 7.00 ppm (T, J=8 Hz, H aromatic meta COS)-2H at 7.30 ppm (S.e., NH₂ thiazole)-1H at 6.70 ppm (S, H thiazole)-1H at 5.70 ppm (D of D, J₁ =9 Hz, J₂ =4 Hz, H₇)-1H at 5.05 ppm (D, J=4 Hz, H₆)-1H at 4.25 ppm and 1H at 3.93 ppm (D, J=13 Hz, CH₂ SCO)-3H at 3.80 ppm (S, CH₃ ON)-1H at 3.67 ppm and 1H at 3.32 ppm (D, J=17 Hz, CH₂ S)-3H at 3.01 ppm (M, ##STR115## at 1.21 ppm (D, J=7 Hz,

NMR n° 76

1H at 10.55 ppm (S, Ar NHCO)-1H at 9.53 ppm (D, J=9 Hz, CONH)-2H at 7.84 ppm (D, J=8 Hz, H aromatics ortho COS)-3H at 7.80 ppm (S.e., CH₂ N⁺ H₃)-2H at 7.71 ppm (D, J=8 Hz, H aromatics meta COS)-2H at 7.30 ppm (S.e., NH₂ thiazole)-1H at 6.71 ppm (S, H thiazole)-1H at 5.72 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇)-1H at 5.08 ppm (D, J=4 Hz, H₆)-1H at 4.26 ppm and 1H at 3.92 ppm (D, J=13 Hz, CH₂ SCO)-3H at 3.79 ppm (S, CH₃ ON)-1H at 3.70 ppm and 1H at 3.34 ppm (D, J=17 Hz, CH₂ S)-2H at 3.05 ppm (M, CH₂ N⁺ H₃)-2h at 2.70 ppm (M, CH₂ CH₂ N⁺ h₃.

NMR n° 77

1H at 10.95 ppm (ArNHCO)-1H at 9.55 ppm (D, J=9 Hz, CONH)-2H at 8.90 ppm (S.e., NH₂ --CH₃)-2H at 7.95 ppm (D, J=8 Hz, H aromatics ortho SCO)-2H at 7.75 ppm (D, J=8 Hz, H aromatics meta SCO)-2H at 7.30 ppm (S.e., NH₂ thiazole 1H at 6.70 ppm (S, H thiazole)-1H at 5.70 ppm (D of D, J₁ =9 Hz, J₂ =4 Hz, H₇)-1H at 5.08 ppm (D, J=4 Hz, H₆)-1H at 4.30 ppm (D, J=13 Hz, CH₂ SCO)-3H at 3.90 ppm (M, CH₂ N⁺ and CH₂ SCO)-3H at 3.80 ppm (S, NOCH₃)-1H at 2.65 ppm (D, J=17 Hz, CH₂ S)-1 H at 3.40 ppm (D, J=17 Hz, CH₂ S)-3H at 2.60 ppm (S.e., --N⁺ H₂ --CH₃)-.

NMRn° 78

1H at 10.12 ppm (S, ArNHCO)-1H at 9.39 ppm (D, J=9 Hz, NHCO)-1H at 7.90 ppm (D, J=8 Hz, H aromatics ortho SCO)-3H at 7.80 ppm S.e., CH₂ N⁺ H₃)-2H at 7.75 ppm (D, J=8 Hz, H aromatics meta SCO)-2H at 7.50 ppm (S.e., NH₂ thiazole)-1H at 6.71 ppm (S, H thiazole)-1H at 5.76 ppm (D of D, J₁ =9 Hz, J₂ =4 Hz, H₇)-1H at 5.11 ppm (D, J=4 Hz, H₆)-1H at 4.22 ppm (D, J=13 Hz, CH₂ SCO)-1H at 3.93 ppm (D, J=13 Hz, CH₂ SCO)-1H at 3.71 ppm (D, J=17 Hz, CH₂ S)-1H at 3.45 ppm (D, J=17 Hz, CH₂ S)-2H at 3.07 ppm (M, CH₂ N⁺ H₃)-2H at 2.73 ppm (M, CH₂ CH₂ N⁺ H₃)-6H at 1.14 ppm (S, ##STR116##

NMRn° 79

1H at 9.45 ppm (D, J=9 Hz, CONH)-1H at 8.58 ppm (S, H thiazole ester)-3H at 8.53 ppm (S.e., CH₂ N⁺ H₃)-2H at 7.50 ppm (S.e. NH₂ thiazole)-1H at 6.70 ppm (S, H thiazole)-1H at 5.80 ppm (D of D, J₁ =9 Hz, J₂ =4 Hz, H₇)-1H at 5.20 ppm (D, J=4 Hz, H₆)-2H at 4.50 ppm (S.e., CH₂ N⁺ H₃)-1H at 4.20 ppm (D, J=13 Hz, CH₂ SCO)-1H at 3.90 ppm (D, J=13 Hz, CH₂ SCO)-1H at 3.71 ppm (D, J=17 Hz, CH₂ S)-1H at 3.38 ppm (D, J=17 Hz, CH₂ S)-6H at 1.42 ppm (S, ##STR117##

NMRn° 80

1H at 9.70 ppm (D, J=9 Hz, CONH)-3H at 8.15 ppm (S.e., CH₂ N⁺ H₃)-2H at 7.45 ppm (S.e., NH₂ thiazole)-2H at 7.40 ppm (D, J=8 Hz, H aromatics meta O)-2H at 7.05 ppm (D, J=8 Hz, H aromatics ortho O)-1H at 6.76 ppm (S, H thiazole)-1H at 5.77 ppm (D of D, J₁ =9 Hz, J₂ =4 Hz, H₇)-1H at 5.12 ppm (D, J=4 Hz, H₆)-2H at 5.00 ppm (S, CH₂ O-Ar)-1H at 4.20 ppm (D, J=13 Hz, CH₂ SCO)-2H at 4.00 ppm (M, CH₂ N⁺ H₃)-3H at 3.85 ppm (S, NOCH₃)-1H at 3.76 ppm (D, J=13 Hz, CH₂ SCO)- 1H at 3.70 ppm (D, J=17 Hz, CH₂ S)-1H at 3.30 ppm (D, J=17 Hz, CH₂ S).

NMRn° 81

1H at 9.42 ppm (D, J=9 Hz, CONH)-3H at 8.07 ppm (S.e., CH₂ N⁺ H₃)-2H at 7.41 ppm (D, J=8 Hz, H aromatics meta O)-2H at 7.40 ppm (S.e., NH₂ thiazole)-2H at 7.00 ppm (D, J=8 Hz, H aromatics ortho O)-1H at 6.66 ppm (S, H thiazole)-1H at 5.80 ppm (D of D, J₁ =9 Hz, J₂ =4 Hz, H₇)-1H at 5.09 ppm (D, J=4 Hz, H₆)-2H at 4.96 ppm (S, CH₂ OAr)-1H at 4.10 ppm (D, J=13 Hz, CH₂ SCO)-2H at 3.80 ppm (M, ArCH₂ N⁺ H₃)-1H at 3.75 ppm (D, J=13 Hz, CH₂ SCO)-1H at 3.60 ppm (D, J=17 Hz, CH₂ S)-1H at 3.30 ppm (D, J=17 Hz, CH₂ S)-6H at 1.41 ppm (2S, ##STR118##

NMRn° 82

1H at 10.56 ppm (S, ArNHCO)-1H at 9.55 ppm (D, J=9 Hz, CONH)-2H at 7.90 ppm (D, J=8 Hz, H aromatics ortho SCO)-3H at 7.75 ppm (S.e., CH₂ N⁺ H₃)-2H at 7.70 ppm (D, J=8 Hz, H aromatics meta SCO)-2H at 7.45 ppm (S.e., NH₂ thiazole)-1H at 6.66 ppm (S, H thiazole)-1H at 5.74 ppm (D of D, J₁ =9 Hz, J₂ =4 Hz, H₇)-1H at 5.11 ppm (D, J=4 Hz, H₆)-1H at 4.25 ppm (D, J=13 Hz, CH₂ SCO)-1H at 3.92 ppm (D, J=13 Hz, CH₂ SCO)-2H at 3.84 ppm (D, J=7 Hz, N--OCH₂ --)-1H at 3.66 ppm (D, J= 17 Hz, CH₂ S)-1H at 3.34 ppm (D, J=17 Hz, CH₂ S)-2H at 3.05 ppm (M, CH₂ N⁺ H₃)-2H at 2.68 ppm (T, J=7 Hz, CH₂ CH₂ N⁺ H₃)-1H at 3.05 ppm (M, N--OCH₂ <CH)-2H at 0.46 ppm and 2H at 0.23 ppm (2M, CH₂ cyclopropane).

EXAMPLE 85 7-[2-(2-amino 4-thiazolyl) 2-(2-carboxy 2-propyl oxyimino) acetamido] 3-[(4-piperidyl) carbonylthiomethyl] 3-cepheme 4-carboxylic acid bis trifluoracetate syn isomer (SR 42318) (I) R₁ =R₂ =H R₃ =COOH X=S n=O ##STR119##

(a) 1-tertiobutoxycarbonyl 4-piperidyl thiocarboxylic acid.

This is prepared from 9.16 g of 1-tertiobutoxycarbonyl 4-piperidyl carboxylic acid, according to the method used in example 64a. The crude oily product is used as is.

(b) 7-amino 3-[1-tertiobutoxycarbonyl 4-piperidyl) carbonylthiomethyl] 3-cepheme carboxylic acid.

9 g of 7-aminocephalosporanic acid and 2.8 g of sodium bicarbonate are dissolved in 100 ml of phosphate buffer pH 6.65. The solution is heated to 50° C. under nitrogen atmosphere, then the solution composed of the thioacid obtained above and 3.36 g of sodium bicarbonate in 70 ml of phosphate buffer pH 6.65 is added.

A precipitate forms during the reaction and the pH tends to go up. It is kept to 6.35 by adding a 10% solution of phosphoric acid. After 4 hours, the reaction medium is cooled down to 0° C. and the crystals are drained. Then they are washed in cold water, acetone, ether and finally in hexane.

Weight: 7.5 g

IR Spectrum: γCO βlactam 1810 cm⁻¹.

(c) 7-[2-(2-tritylamino 4-thiazolyl) 2-(2-tertiobutoxycarbonyl 2-propyl oxyimino) acetamido] 3-[(1-tertiobutoxycarbonyl 4-piperidyl) carbonylthiomethyl] 3-cepheme 4-carboxylic acid syn isomer.

11.4 g of the acid obtained above are placed in suspension in 250 ml of anhydrous dichloromethane and the mixture is cooled down to +5° C. A solution of 3.47 ml of triethylamine and 9.5 ml of dimethylaniline in 20 ml of dichloromethane is then added dropwise followed by a solution of 7.94 ml of chlorotrimethylsilane in 10 ml of dichloromethane, also added dropwise. The temperature is allowed to return to around 20° C. and the mixture is left at that temperature for two hours.

The temperature is then brought down again to +5° C., and 14 g of chloride of 2-(2-tritylamino 4-thiazolyl) 2-(2-tertiobutoxycarbonyl 2-propyl oxyimino) acetic acid syn isomer are added in small quantities. The reaction mixture is stirred for 1 hour at ambient temperature, and placed in a refrigerator for 15 hours.

40 ml of water are then added and the dichloromethane is evaporated. The residual is taken up in 600 ml of ethyl acetate and 300 l ml of buffer sulfate pH 2. The organic phase is decanted and washed again with 150 ml of buffer sulfate pH 2, and then with 100 ml of water.

After drying over magnesium sulfate, the organic solution is concentrated to about 150 ml. It is then poured dropwise in 1200 ml of hexane under strong stirring. After 30 minutes of that stirring, the solid product is drained, washed in hexane and dried in vacuo.

20.8 g of the expected product are then obtained.

NMR Spectrum

1H at 9.32 ppm (D, J=9 Hz, CO NH)-1H at 8.80 ppm (S, NH-trityle)-15H at 7.25 ppm (M, H aromatics-trityle)-1H at 6.60 ppm (S, H thiazole)-1H at 5.66 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇)-1H at 5.06 ppm (D, J=4 Hz, H₆)-1H at 4.00 ppm at 1H at 3.75 ppm (D, J13 Hz, CH₂ SCO)-1H at 3.56 ppm at 1H at 3.32 ppm (D, J=17 Hz, CH₂ S)-2H at 3.85 ppm, 3H at 2.75 ppm, 2H at 1.75 ppm and 2H at 1.38 ppm (M, CH and CH₂ piperidine)-2H at 1.34 ppm (2S, COOtBu, N-Boc, --C(CH₃)₂).

(d) SR 42318

The compound obtained above is deprotected by the trifluoracetic acid as indicated in Example 1c. The expected product is obtained in the same way.

NMR Spectrum

1H at 9.40 ppm (D, J=9 Hz, NHCO)-1H at 8.60 ppm at 8.35 ppm (2 S.E., NH₂ ⁺ piperidine)-2H at 7.30 ppm (S.e, NH₂ thiazole)-1H at 6.66 ppm (S, H thiazole)-1H at 5.75 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇)-1H at 5.08 ppm (D, J=4 Hz, H₆)-1H at 4.05 ppm 1H at 3.75 ppm (D, J=13 Hz, CH₂ SCO)-1H at 3.61 ppm (D, J=17 Hz, CH₂ S)-3H at 3.25 ppm (M, CH₂ S and H piperidine αNH₂ ⁺ equatorial)-3H at 2.90 ppm (M, SCO--<CH and H piperidine αNH₂ ⁺ axial)-2H at 1.95 ppm (M, H piperidine βNH₂ ⁺ equatorial)-2H 1.70 ppm (M, H piperidine βNH₂ ⁺ axials)-6H at 1.42 ppm (2S, (CH₃)₂ C).

EXAMPLES 86 to 100

(a) By operating as in Example 85b, but by varying the thioacid, one obtains the 7-amino 3-cepheme 4-carboxylic acids variously substituted in 3, and listed in Table III.

                  TABLE III                                                        ______________________________________                                          ##STR120##                                                                                          ELEMENTARY                                                                     ANALYSIS                                                                  IR Spectrum                                                                               Cal-                                               B'               γCO lactam                                                                          culated  Found                                     ______________________________________                                          ##STR121##      1810 cm.sup.-1                                                                            C: 52,59 H: 5,25 N: 8,76                                                                52,27 5,22 8,40                            ##STR122##      1810 cm.sup.-1                                                                            C: 52,59 H: 5,25 N: 8,76                                                                52,14 5,13 8,72                            ##STR123##      1805 cm.sup.-1                                                                            C: 51,94 H: 6,43 N: 8,65                                                                51,75 6,39 8,38                            ##STR124##      1815 cm.sup.-1                                                                            C: 50,56 H: 5,01 N: 10,72                                                               50,32  5,13 10,59                         ______________________________________                                    

(b) The different products (I)(X=S) listed in Table IV hereafter are obtained with the products prepared according to the method of Example 85c and d, using different acid chlorides.

                                      TABLE IV                                     __________________________________________________________________________      ##STR125##                                                                                                     IR Spectrum                                                                    Compound 7                                    SR No.                                                                             n R.sub.1                                                                           R.sub.2                                                                           R.sub.3                                                                             B               γCO cm.sup.-1                                                                  NMR No.                                 __________________________________________________________________________     42316                                                                              O H  H  H                                                                                    ##STR126##     1790-1730 1690                                                                       83                                      42317                                                                              O H  H  H                                                                                    ##STR127##     1790-1720                                                                            84                                      42319                                                                              O CH.sub.3                                                                          CH.sub.3                                                                          COOH                                                                                 ##STR128##     1795-1720                                                                            85                                      42802                                                                              O CH.sub.3                                                                          CH.sub.3                                                                          COOH                                                                                 ##STR129##     1790-1720 1690                                                                       86                                      42889                                                                              O H  H  H                                                                                    ##STR130##     1790-1710                                                                            87                                      42882                                                                              O CH.sub.3                                                                          CH.sub.3                                                                          COOH                                                                                 ##STR131##     1790-1715                                                                            88                                      43017                                                                              O (CH.sub.2).sub.3                                                                     COOH                                                                                 ##STR132##     1790-1715 1690                                                                       89                                      43019                                                                              O H  CH.sub.3                                                                          COOH                                                                                 ##STR133##     1790-1720 1690                                                                       90                                      43020                                                                              O H  H  COOH                                                                                 ##STR134##     1790-1715 1690                                                                       91                                      43021                                                                              O H  H                                                                                  ##STR135##                                                                          ##STR136##     1790-1685                                                                            92                                      43023                                                                              O H  H  H                                                                                    ##STR137##     1790-1690                                                                            93                                      43520                                                                              O H  H  H                                                                                    ##STR138##     1785-1690 (Methylyne chloride)                                                       94                                      43522                                                                              O H  H                                                                                  ##STR139##                                                                          ##STR140##     1785-1690 (Methylene chloride)                                                       95                                      43524                                                                              O CH.sub.3                                                                          CH.sub.3                                                                          COOH                                                                                 ##STR141##     1785-1715 (Methylene chloride)                                                       96                                      43697                                                                              O H  H  COOH                                                                                 ##STR142##     1785-1715                                                                            97                                      __________________________________________________________________________

NMR n° 83

1H at 9.50 ppm (D, J=9 Hz, CO NH)-1H at 8.70 ppm and 1H at 8.45 ppm (2 S.e., NH₂ ⁺ piperidine)-2H at 7.30 ppm (S.e., NH₂ thiazole)-1H at 6.71 ppm (S, H thiazole)-1H at 5.76 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇)-1H at 5.07 ppm (D, J=4 Hz, H₆)-1H at 4.05 ppm (D, J=13 Hz, CH₂ SCO)-4H at 3.78 ppm (M, CH₃ ON and CH₂ SCO)-1H at 3.58 ppm (D, J=17 Hz, CH₂ S)-3H at 3.27 ppm (M, CH₂ S and H equatorials piperidine αNH₂ ⁺)-3H at 2.95 ppm (M, SCO--<CH and H axials piperidine αNH₂ )-2H at 2.00 ppm and 2H and 1.70 ppm (M, H piperidine βNH₂ ⁺).

NMR n° 84

1H at 9.50 ppm (D, J=9 Hz, CO NH)-3H at 8.40 ppm (S.e., CH₂ NH₃ ⁺)-2H at 7.95 ppm (D, J=7 Hz, H aromatics ortho CO)-2H at 7.55 ppm (D, J=7 Hz, H aromatics meta CO)-2H at 7.30 ppm (S.e., NH₂ thiazole)-1H at 6.73 ppm (S, H thiazole)-1H at 5.71 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇)-1H at 5.08 ppm (D, J=4 Hz, H₆)-1H at 4.26 ppm (D, J13 Hz, CH₂ SCO)-2H at 4.12 ppm (M, CH₂ N⁺ H₃)-1H at 3.92 ppm (D, J=13 Hz, CH₂ SCO)-3H at 3.78 ppm (S, NOCH₃)-1H at 3.68 ppm (D, J=17 Hz, CH₂ S)-1H at 3.40 ppm (D, J=17 Hz, CH₂ S).

NMRn° 85

1H at 9.45 ppm (D, J=9 Hz, NHCO)-3H at 8.25 ppm (S.e., CH₂ NH₃ ⁺)-2H at 7.95 ppm (D, J=7 Hz, H aromatics ortho CO)-2H at 7.55 ppm (D, J=7 Hz, H aromatics meta CO)-2H at 7.20 ppm (S.e., NH₂ thiazole)-1H at 6.68 ppm (S, H thiazole)-1H at 5.79 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇)-1H at 5.10 ppm (D, J=4 Hz, H₆)-1H at 4.27 ppm (D, J=13 Hz, CH₂ SCO)-2H at 4.10 ppm (M, CH₂ N⁺ H₃)-1H at 3.95 ppm (D, J=13 Hz, CH₂ SCO)-1H at 3.69 ppm (D, J=17 Hz, CH₂ S)-1H at 3.40 ppm (D, J=17 Hz, CH₂ S)-6H at 1.40 ppm (2S, (CH₃)₂ C).

NMR 86

1H at 9.45 ppm (D, J=9 Hz, NHCO)-3H at 7.75 ppm (S.e., CH₂ NH₃ ⁺)-2H at 7.45 ppm (S.e., NH₂ thiazole)-1H at 6.70 ppm (S, H thiazole)-1H at 5.80 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇)-1H at 5.20 ppm (D, J=4 Hz, H₆)-1H at 4.00 ppm and 1H at 3.74 ppm (D, J=13 Hz, CH₂ SCO)-1H at 3.60 ppm (D, J=17 Hz, CH₂ S)-1H at 3.25 ppm (D, J=17 Hz, CH₂ S)-2H at 2.60 ppm (M, CH₂ N⁺)-1H at 2.45 ppm (M, SCO<CH)-4H at 1.85 ppm, 3H at 1.40 ppm and 2H at 1.00 ppm (M, H cyclohexane)-6H at 1.40 ppm (2S, (CH₃)₂ C).

NMRn° 87

1H at 9.55 ppm (D, J=9 Hz, NHCO)-3H at 8.35 ppm (S.e., CH₂ NH₃ ⁺)-1H at 8.05 ppm (S, H aromatic ortho COS and ortho CH₂ NH₃ ⁺)-1H at 7.90 ppm (D, J=8 Hz, H aromatic ortho COS and para CH₂ N⁺ H₃)-1H at 7.72 ppm (D, J=8 Hz, H aromatic para COS)-1H at 7.55 ppm (T, J=8 Hz, H aromatic meta COS)-1H at 6.72 ppm (S, H thiazole)-1H at 5.74 ppm (D of D, J₁ =9 Hz, J₂ =4 Hz, H₇)-1H at 5.08 ppm (D, J=4 Hz, H₆)-1H at 4.30 ppm (D, J=13 Hz, CH₂ SCO)-2H at 4.10 ppm (M, Ar CH₂ N⁺ )-1H at 3.95 ppm (D, J=13 Hz, CH₂ SCO)-3H at 3.80 ppm (S, CH₃ ON)-1H at 3.70 ppm and 1H at 3.40 ppm (D, J=17 Hz, CH₂ S).

NMRn° 88

1H at 9.42 ppm (D, J=9 Hz, CO NH)-3H at 8.25 ppm (S.e., CH₂ N⁺ H₃)-1H at 8.00 ppm (S, H aromatic ortho COS et ortho CH₂ N⁺)-1H at 7.88 ppm (D, J=8 Hz, H aromatic ortho COS and para CH₂ N⁺)-1H at 7.75 ppm (D, J=8 Hz, H aromatic para COS)-1H at 7.55 ppm (T, J=8 Hz, H aromatic meta COS)-2H at 7.40 ppm (S.e., NH₂ thiazole)-1H at 6.67 ppm (S, H thiazole)-1H at 5.81 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇)-1H at 5.12 ppm (D, J=4 Hz, H₆)-1H at 4.30 ppm (D, J=13 Hz, CH₂ SCO)-2 H at 4.08 ppm (M, Ar CH₂ N⁺)1H at 3.95 ppm (D, J=13 Hz, CH₂ SCO)-1H at 3.71 ppm et 1H at 3.40 ppm (D, J=17 Hz, CH₂ S)-6H at 1.43 ppm (2S, (CH₃)₂ C).

NMR n° 89

1H at 9.50 ppm (D, J=9 Hz, CO NH)-3H at 7.75 ppm (S.e., CH₂ NH₃ ⁺)-2H at 7.30 ppm (S.e., NH₂ thiazole)-1H at 6.70 ppm (S, e,uns/H/ thiazole)-1H at 5.81 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇)-1H at 5.14 ppm (D, J=4Hz, H₆)-1H at 4.02 ppm and 1H at 3.74 ppm (D, J=13 Hz, CH₂ SCO)-1H at 3.63 ppm and 1Hz at 3.27 ppm (D, J=17 Hz, CH₂ S)-2H at 2.58 ppm (M, CH₂ N⁺)-1H at 2.50 ppm (M, SCO--<CH)-4H at 2.30 ppm (M ##STR143## 6H at 1.85 ppm, 1H at 1.45 ppm, 2H at 1.25 ppm and 2H at 0.95 ppm (M, ##STR144## and CH and CH₂ cyclohexane)-.

NMR n° 90

1H at 9.45 ppm (2D, J=9 Hz, CONH) -3H at 7.75 ppm (S.e., CH₂ N⁺ H₃)-2H at 7.25 ppm (S, e., NH₂ thiazole)-1H at 6.70 ppm (S, H thiazole)-1H at 5.80 ppm (2Q, J₁ =9 Hz J₂ =4 Hz, H₇) -1H at 5.10 ppm (D, J=4 Hz, H₆)-1H at 4.56 ppm (Q, J=7 Hz, ##STR145## at 4.00 ppm and 1H at 3.74 ppm (D, J=13 Hz, CH₂ SCO)-1H at 3.60 ppm and 1H at 3.22 ppm (D, J=7 Hz, CH₂ S)-2H at 2.60 ppm (M, CH₂ N⁺ H₃)-1H at 2.50 ppm (M, SCO--<CH)-4H at 1.80 ppm, 1H at 1.44 ppm, 2H at 1.30 ppm and 2H at 1.00 ppm (M, H cyclohexane)-3H at 1.36 ppm (D, J=7 Hz, ##STR146##

NMR n° 91

1H at 9.50 ppm (D, J=9 Hz, CO NH)-3H at 7.82 ppm (S, e., CH₂ N⁺ H₃)-2H at 7.30 ppm (S.e., NH₂ thiazole)-1H at 6.76 ppm (S, H thiazole)-1H at 5 74 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇)-1H at 5.08 ppm (D, J=4 Hz, H₆)-2H at 4.52 ppm (S, N O CH₂ -COOH)-1H at 4 00 ppm and 1H at 3.71 ppm (D, J=13 Hz, CH₂ SCO)-1H at 3.56 ppm and 1H at 3.21 ppm (D, J=17 Hz, CH₂ S)-2H at 2.58 ppm (M, CH₂ NH₃ ⁺)-1H at 2.51 ppm (M, SCO<CH)-4H at 1.90 ppm, 1H at 1.45 ppm, 2H at 1.30 ppm et 2H at 0.95 ppm (M, H cyclohexane)-

NMR n° 92

1H at 9.55 ppm (D, J=9 Hz, CONH)-3H at 7.80 ppm (S.e., CH₂ NH₃ ⁺)-2H at 7.23 ppm (S.e., NH₂ thiazole)-1H at 6.68 ppm (S, H thiazole)-1H at 5.73 ppm (D of D, J₁ =9 Hz J₂ =4 Hz, H₇)-1H at 5.06 ppm (D, J=4 Hz, H₆)-1H at 4.00 ppm and 1H at 3.70 ppm (D, J=13 Hz, CH₂ SCO)-2H at 3.90 ppm (D, J=7 Hz, N-O-CH₂ -)-1H at 3.60 ppm and 1H at 3.23 ppm (D, J=17 Hz, CH₂ S)-2H at 2.58 ppm (M, CH₂ N⁺ H₃)-1H at 2.51 ppm (M, SCO--<CH)-4H at 1.85 ppm, 1H at 1.44 ppm, 2H at 1.30 ppm and 2H at 0.95 ppm (M, H cyclohexane)-1H at 1.08 ppm, 2H at 0.45 ppm and 2H at 0.23 ppm (H cyclopropane)-.

NMR n° 93

1H at 9.55 ppm (D, J=9 Hz, CONH)-3H at 7.80 ppm (S.e., CH₂ NH₃ ⁺)-2H at 7.20 ppm (S.e., NH₂ thiazole)-1H at 6.69 ppm (S, H thiazole)-1H at 5.68 ppm (D of D, J₁ =9 Hz, J₂ =H Hz, H₇)-1H at 5.05 ppm (D, J=4 Hz, H₆)-1H at 4.00 ppm and 1H at 3.70 ppm (D, J=13 Hz, CH₂ SCO)-3H at 3.75 ppm (S, CH₃ ON)-1H at 3.60 ppm and 1H at 3.25 ppm (D, J=17 Hz, CH₂ S)-2H at 2.57 ppm (M, CH₂ NH₃ ⁺)-1H at 2.50 ppm (M, SCO--<CH)-4H at 1.90 ppm, 1H at 1.47 ppm, 2H at 1.30 ppm and 2H at 0.97 ppm (M, H cyclohexane)-.

NMR n° 94

1H at 10.80 ppm (S, ArNHCO)-1H at 9.55 ppm (D, J=9 Hz, NHCO)-3H at 8.16 ppm (S.e., CH₂ N⁺ H₃)-2H at 7.92 ppm (D, J=8 Hz, H aromatics ortho SCO)-2H at 7.75 ppm (D, J=8 Hz, aromatics meta SCO)-2H at 7.35 ppm (S.e., NH₂ thiazole)-1H at 6.67 ppm (S, H thiazole)-1H at 5.80 ppm (D of D, J₁ =9 Hz, J₂ =4 Hz, H₇)-1H at 5.08 ppm (D, J=4 Hz, H₆)-1H at 4.26 ppm (D, J=13 Hz, CH₂ SCO)-1H at 3.91 ppm (D. J=13 Hz, CH₂ SCO)-3H at 3.80 ppm (S, CH₃ ON)-1H at 3.67 ppm (D, J=17 H, CH₂ S)-1 H at 3.32 ppm (D, J=17 Hz, CH₂ S)-.

NMR n° 95

1H at 10.84 ppm (S, ArNHCO)-1H at 9.57 ppm (D, J=9 Hz, NHCO)-3H at 8.15 ppm (S.e., CH₂ N⁺ H₃)-2H at 7.95 ppm (D, J=8 Hz, H aromatics ortho SCO)-2H at 7.74 ppm (D, J=8 Hz, H aromatics metal SCO)-2H at 7.55 ppm (S.e., NH₂ thiazole)-1H at 6.66 ppm (S, H thiazole)-1H at 5.80 ppm (D of D, J₁ =9 Hz, J₂ =4 Hz, H₇)-1H at 5.10 ppm (D, J=4 Hz, H₆)-1H at 4.25 ppm (D, J=13 Hz, CH₂ SCO)-1H at 3.95 ppm (D, J=13 Hz, CH₂ SCO)-2H at 3.84 ppm (D, J=7 Hz, N--O--CH₂ --)-2H at 3.82 ppm (M, CH₂ N.sup. + H₃)-1H at 3.66 ppm (D, J=17 Hz, CH₂ S)-1H at 3.34 ppm (D, J=17 Hz, CH₂ S)-1H at 1.10 ppm (M, N--O--CH₂ --<CH)-2H at 0.55 ppm and 2H at 0.23 ppm (CH₂ cyclopropane)-.

NMR n° 96

1H at 10.85 ppm (S, ArNHCO)-1H at 9.45 ppm (D, J=9 Hz, CONH)-3H at 8.15 ppm (S.e., CH₂ N⁺ H₃)-2H at 7.92 ppm (D, J=8 Hz, H aromatics ortho SCO)-2H at 7.75 ppm (D, J=8 Hz, H aromatics meta SCO)-2H at 7.50 ppm (S.e., NH₂ thiazole)-1H at 6.68 ppm (S, H thiazole)-1H at 5.79 ppm (D of D, J₁ =9 Hz, J₂ =4 Hz, H₇)-1H at 5.12 ppm (D, J=4 Hz, H₆)-1H at 4.30 ppm (D, J=13 Hz, CH₂ SCO)-1H at 3.92 ppm (D, J=13 Hz, CH₂ SCO)-2H at 3.79 ppm (M, CH₂ N⁺ H₃)-1H at 3.67 ppm (D, J=17 Hz, CH₂ S)-1H at 3.34 ppm (D, J=17 Hz, CH₂ S)-6H at 1.41 ppm (2S, ##STR147##

NMR n° 97

1H at 10.82 ppm (S, ArNHCO)-1H at 9.47 ppm (D, J=9 Hz, NHCO)-3H at 8.10 ppm (S.e., CH₂ N⁺ H₃)-2H at 7.95 ppm (D, J=8 Hz, H aromatics ortho SCO)-2H at 7.72 ppm (D, J=8 Hz, H aromatics metal SCO)-2H at 7.20 ppm (S.e., NH₂ thiazole)-1H at 6.74 ppm (S, H thiazole)-1H at 5.76 ppm (D of D, J₁ =9 Hz, J₂ =4 Hz, H₇)-1H at 5.08 ppm (D, J=4 Hz, H₆)-2H at 4.55 ppm (S, CH₂ ON)-1H at 4.27 ppm (D, J=13 Hz, CH₂ SCO)-1H at 3.92 ppm (D, J=13 Hz, CH₂ SCO)-2H at 3.81 ppm (S.e., CH₂ N⁺ H₃)-1H at 3.71 ppm (D, J=17 Hz, CH₂ S)-1H at 3.40 ppm (D, J=17 Hz, CH₂ S)-.

The products according to the invention have been tested as regards their pharmacological properties and more particularly their bacteriostatic action. This action was determined in vitro by the dilutions method. The test was conducted both on positive Gram strains and no negative Gram strains.

The results, expressed in minimum inhibiting concentrations (CMI - μg/ml), are given in Table V.

                                      TABLE V                                      __________________________________________________________________________     STRAINS                                                                        Products    Escherichia                                                                           Escherichia        Proteus     Pseudomonas                  SR   Smith Staphy-                                                                         Coli   Coli  Klebsiella                                                                           Enterbactor                                                                           morganii                                                                            Providencia                                                                           aeruginosa                   no   lococcus                                                                              Col E.sub.1 Amp                                                                       Sol RL 90                                                                            R 30  R 046  1510 155    NCTC 8203                    __________________________________________________________________________     42317                                                                               0,25   --     1     8     1      8    1      16                           42319                                                                               4      --     4     1     16     16   2      2                            42800                                                                               8      0,0625 0,5   0,25  64     8    0,5    2                            42801                                                                               4      ≦0,0312                                                                        0,5   0,25  16     2    1      2                            42802                                                                               4      0,0625 0,5   0,5   --     32   4      2                            42803                                                                               4      0,0625 1     0,25  64     16   1      2                            42804                                                                               8      0,0625 1     0,5   64     16   1      2                            42808                                                                               2      0,25   1     0,5   64     16   1      1                            42809                                                                               2      0,0625 1     0,5   64     16   1      1                            42883                                                                               0,125  0,0625 1     2     16     2    1      8                            42885                                                                               25     ≦0,0312                                                                        0,25  2     32     2    0,5    2                            42889                                                                               0,125  ≦0,0312                                                                        1     2     16     8    2      32                           42893                                                                               0,125  0,125  0,125 2     8      2    1      8                            42895                                                                               0,5    ≦0,0312                                                                        0,125 2     8      2    2      8                            42897                                                                               0,5    ≦0,0312                                                                        0,125 1     8      2    1      8                            42880                                                                               8      0,0625 1     2     64     16   1      4                            42882                                                                               2      0,0625 1     0,5   64     32   1      8                            42943                                                                               2      0,0625 1     1     64     32   2      8                            42946                                                                               1      ≦0,0312                                                                        0,25  2     16     2    1      8                            42965                                                                               1      ≦0,0312                                                                        0,125 0,5   4      1    0,125  2                            42967                                                                               0,125  0,0625 1     16    32     8    2      16                           43015                                                                               4      0,0625 2     1     --     16   1      4                            43016                                                                               2      0,0625 0,25  0,5   32     8    0,5    2                            43019                                                                               4      ≦0,0312                                                                        1     1     64     32   1      2                            43027                                                                               0,125  ≦0,0312                                                                        1     --    32     8    1      2                            43029                                                                               0,5    0,0625 0,5   2     16     2    1      16                           43147                                                                               1      ≦0,0312                                                                        0,25  1     16     2    0,5    8                            43179                                                                               0,5    0,0625 1     1     8      1    1      16                           43183                                                                               1      ≦0,0312                                                                        0,125 1     16     1    0,5    16                           43185                                                                               1      ≦0,0312                                                                        0,25  2     16     2    1      4                            43187                                                                               0,125  ≦0,0312                                                                        0,25  2     16     2    1      4                            43189                                                                               0,125  ≦0,0312                                                                        0,125 4     16     2    0,5    1                            43191                                                                               0,125  ≦0,0312                                                                        1     16    32     8    1      4                            43226                                                                               0,25   ≦0,0312                                                                        0,125 1     8      1    0,25   2                            43323                                                                               1      ≦ 0,0312                                                                       0,5   1     16     2    1      8                            43336                                                                               1      ≦0,0312                                                                        0,5   2     32     2    0,5    16                           43417                                                                               0,5    ≦0,0312                                                                        0,25  1     8      1    0,5    4                            43419                                                                               0,5    ≦0,0312                                                                        0,5   2     8      2    1      8                            43464                                                                               1      ≦0,0312                                                                        0,25  2     16     2    1      16                           43520                                                                               0,125  0,0625 0,5   8     32     8    1      2                            43559                                                                               0,5    ≦0,0312                                                                        0,125 1     8      1    0,5    2                            43666                                                                               0,5    ≦0,0312                                                                        0,5   4     32     4    1      4                            __________________________________________________________________________

The results given in Table V show that the products according to the invention have a wide spectrum of activity, both on positive Gram bacteria and on negative Gram bacteria.

Moreover, according to the tests conducted on animals, the toxicity of these products appears to be sufficiently small to allow their use in therapeutics.

The products according to the invention can therefore be used as antibiotics in human and veterinary medicine. They have a wide spectrum and can be used in all bacterial infections with sensitive germs.

The products can be administrated by general route (perenteral or oral) or by local route.

The pharmaceutical compositions are produced from compounds (I) in a soluble form obtained by salification of one of the acid functions of the molecule or of one of the amine functions of chain B.

The pharmaceutical compositions containing, as active ingredient, the antibiotic according to the invention in combination with a pharmaceutically acceptable vehicle, may be solid or liquid; for example, they may be presented as injectable preparations, as tablets, gelules, granules, ointments, creams, gels or suppositories. Their posology may vary in a wide proportion, depending in particular on the type of gravity of the injection to be treated and depending on the mode of administration. In an adult, the posology is mostly between 0.250 g and 4 g per day by injectable route.

As an example of galenic preparation, it is possible to prepare an injectable solution, for every ampulla:

    ______________________________________                                         SR 43189                 1      g                                              Water for injectable prepara-                                                                           5      ml                                             tion                                                                           Sodium carbonate s.q. for pH =                                                                          6.3.                                                  ______________________________________                                     

We claim:
 1. Celphalosporin compounds of the general formula: ##STR148## in which: x is an oxygen atom or a sulfur atomR₁, R₂, and R₃ each designate, a hydrogen atom or else R₁ and R₂ designate a hydrogen atom or a methyl group, and R₃ designates a carboxyl or cyclopropyl group or else R₁ and R₂ taken together with the carbon atom to which they are linked form a cyclobutyl or cyclopentyl group and R₃ is a carboxyl group, B is the residue of a primary or secondary amine selected from the following groups:Z--NH₂ where Z is an alkylene group with a straight or branched chain having from 2 to 7 carbon atoms, possibly interrupted by a sulfur atom, or else Z is a 1,3-cyclohexylene or 1,4 cyclohexylene group and n is zero, 1 or 2, Z'--Alk--NH--R where Z' is a 1,2-phenylene or 1,3-phenylene or 1,4-phenylene group possibly substituted by 1, 2 or 3 methyl groups or else Z' is a 1,2-cyclohexylene, pb 1,3-cyclohexylene or 1,4-cyclohexylene group, n is 1 or 2, Alk is a straight or branched alkyl group having from 2 to 3 carbon atoms, possibly interrupted by a sulfur atom, and R is a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms, ##STR149## where Z" is a 1,3 phenylene or 1,4 phenylene group, Y is an alkyl group (CH₂)_(m) in which m=1,2 or 3, R' is hydrogen or methyl, n is zero, 1 or 2 and R is as defined above, --Z"--CO--NH--Y--NH₂ where Z" and Y are as defined above and n is zero, 1 or 2, --Z"--Y'--NH--CO--Y--NH₂ where Z" and Y are as defined above and Y' is a straight or branched alkyl group with 1 or 2 carbon atoms, ##STR150## where O=0 or 1, n is zero, 1 or 2 and Y is as defined above, a 2-piperidyl, 3-piperidyl or 4-piperidyl group possibly substituted in the nitrogen atom by a --CO--Y--NH₂ group where Y is as defined above and n is zero, 1 or 2, a group ##STR151## wherein n is zero, 1 or 2, the bicyclic group ##STR152## wherein n is zero, 1 or 2, as well as the pharmaceutically acceptable salts and esters thereof.
 2. Antibiotic composition containing a cephalosporin derivative as claimed in claim 1, in combination with a pharmaceutically acceptable vehicle. 